VCV000007109.156 - ClinVar

NM_000492.4(CFTR):c.350G>A (p.Arg117His)

Germline

Top reviewed classifications are shown here.

Submission summary:

42 submissions

38 submitters

10 conditions

Practice guidelines

Pathogenic

Mar 2004 by American Colle…

for Cystic fibrosis

Reviewed by expert panel

Drug response

Mar 2021 by PharmGKB

for ivacaftor response - Efficacy

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Haplotype

NM_000492.3(CFTR):c.[350G>A;1210-12[5]]

Identifiers

NM_000492.4(CFTR):c.350G>A (p.Arg117His)

Variation ID: 7109 Accession: VCV000007109.156

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117530975 (GRCh38) [ NCBI UCSC ] 7: 117171029 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 6, 2014	Oct 20, 2024	Mar 3, 2004

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.350G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Arg117His	missense
NC_000007.14:g.117530975G>A
NC_000007.13:g.117171029G>A
NG_016465.4:g.70192G>A
LRG_663:g.70192G>A
LRG_663t1:c.350G>A	LRG_663p1:p.Arg117His
	P13569:p.Arg117His

... more HGVS ... less HGVS

Protein change

R117H

Other names

Canonical SPDI

NC_000007.14:117530974:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00163

Links

Genetic Testing Registry (GTR): GTR000576392 UniProtKB: P13569#VAR_000122 OMIM: 602421.0005 dbSNP: rs78655421 Genetic Testing Registry (GTR): GTR000074114 Genetic Testing Registry (GTR): GTR000257096 Genetic Testing Registry (GTR): GTR000500233 Genetic Testing Registry (GTR): GTR000556535 ClinGen: CA221026 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CFTR		-	-	GRCh38 GRCh37	3826	5201

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cystic fibrosis	Pathogenic (18)	practice guideline	Mar 3, 2004	RCV000007528.52
Congenital bilateral aplasia of vas deferens from CFTR mutation	Pathogenic (1)	no assertion criteria provided	Nov 1, 2009	RCV000007529.12
not provided	Pathogenic/Likely pathogenic (14)	criteria provided, multiple submitters, no conflicts	Apr 1, 2024	RCV000078997.72
ivacaftor response - Efficacy	drug response (1)	reviewed by expert panel	Mar 24, 2021	RCV000417156.12
Bronchiectasis with or without elevated sweat chloride 1 Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Hereditary pancreatitis	Pathogenic (1)	criteria provided, single submitter	Apr 13, 2022	RCV000763151.11
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 24, 2018	RCV000826137.13
CFTR-related disorder	Pathogenic (2)	criteria provided, single submitter	Jan 29, 2018	RCV001009478.12
Obstructive azoospermia	Pathogenic (1)	criteria provided, single submitter	Aug 23, 2021	RCV001642199.10
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (1)	criteria provided, single submitter	Mar 30, 2024	RCV003473001.2
Pseudomonas aeruginosa, susceptibility to chronic infection by, in cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	Mar 14, 2024	RCV004018585.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
pathogenic (Mar 03, 2004)	practice guideline (Guideline for cystic fibrosis carrier screening) Method: curation	Cystic fibrosis (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	American College of Medical Genetics and Genomics (ACMG) Study: The ACMG recommended carrier screening panel Accession: SCV000071404.2 First in ClinVar: Jun 04, 2013 Last updated: Feb 06, 2014	Publications: PubMed (1) PubMed: 11280952 pmc: 3110945 pmc: 3110945 Comment: Converted during submission to Pathogenic.
drug response Drug-variant association: Efficacy (Mar 24, 2021)	reviewed by expert panel (Pharmacogenomics knowledge for personalized medicine) Method: curation	ivacaftor response - Efficacy Drug used for Cystic Fibrosis Affected status: yes Allele origin: germline	PharmGKB Accession: SCV000494724.3 First in ClinVar: Feb 19, 2017 Last updated: Dec 12, 2021 Comment: Drug is not necessarily used to treat response condition	Publications: PubMed (5) PubMed: 23891399‚ 25698453‚ 26070913‚ 26324139‚ 28419121 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166157519 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1447964187 Comment: PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or … (more) PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C93, HLA-B57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. (less)
Pathogenic (Apr 23, 2014)	criteria provided, single submitter (Courtagen Life Sciences Classifications) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Courtagen Diagnostics Laboratory, Courtagen Life Sciences Accession: SCV000236522.2 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015
Pathogenic (Feb 11, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281214.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016
Pathogenic (May 07, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329245.7 First in ClinVar: Dec 06, 2016 Last updated: Mar 13, 2019	Comment: The R117H variant in the CFTR gene has been reported multiple times previously as a common variant in the CFTR gene (Moskowitz et al., 2008). … (more) The R117H variant in the CFTR gene has been reported multiple times previously as a common variant in the CFTR gene (Moskowitz et al., 2008). R117H is a class IV variant which results in defective protein conductance but allows for some residual CFTR function (De Boeck et al., 2014). The severity of disease in individuals with one or two R117H pathogenic variants depends on the presence of a variation in the intron 8 poly T tract and the length of the TG tract in cis configuration with the R117H variant (Moskowitz et al., 2008). A longer TG tract in association with a shorter poly T tract has the strongest adverse effect on intron 8 splicing and are associated with more severe disease (Moskowitz et al., 2008). Individuals with a CFTR pathogenic variant in trans with the R117H variant and 5T variant usually develop the lung disease of CF, but individuals with R117H and the 7T variant or the 9T variant have a highly variable phenotype ranging from clinically asymptomatic to congenital absence of the vas deferens (CAVD) and/or non-classic cystic fibrosis (Moskowitz et al., 2008). Given the available information, we interpret R117H as a pathogenic variant. (less)
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	CFTR-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000916176.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (4) PubMed: 11280952‚ 7506096‚ 11491164‚ 23974870 Comment: The CFTR c.350G>A (p.Arg117His) variant is included within the American College of Medical Genetics and Genomics (ACMG) recommended carrier screening panel for cystic fibrosis (Grody … (more) The CFTR c.350G>A (p.Arg117His) variant is included within the American College of Medical Genetics and Genomics (ACMG) recommended carrier screening panel for cystic fibrosis (Grody et al. 2001). There are multiple clinical implications for the p.Arg117His variant that are dependent on the length of the intron 8 polythymidine tract (polyT) region within the CFTR gene. Kiesewetter et al. (1993) and Massie et al. (2001) assessed the influence of the intron-8 polythymidine sequence (IVS8) on the relationship between the genotype and phenotype of individuals with the p.Arg117His variant. They found that when the p.Arg117His variant was found in cis with five thymidines (5T), and in trans to a pathogenic CF variant, the individual was most commonly affected with classic CF. When the p.Arg117His variant was identified in cis with seven thymidines (7T) and in trans to a pathogenic CF variant, male individuals were often affected with congenital absence of the vas deferens (CAVD), and males and females often presented with a milder variation of CF. In the CFTR2 database, the variant was found in 793 CF patients (808 alleles) and was classified as a mutation of varying clinical consequence (Sosnay et al. 2013). The p.Arg117His variant is reported at a frequency of 0.00256 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Arg117His variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (May 15, 2017)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000330915.4 First in ClinVar: Dec 06, 2016 Last updated: Jul 31, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR Number of individuals with the variant: 19 Sex: mixed
Pathogenic (Oct 24, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Cystic fibrosis Congenital bilateral absence of vas deferens (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967658.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Publications: PubMed (6) PubMed: 11491164‚ 7506096‚ 18456578‚ 24440181‚ 15371902‚ 19092437 Comment: The p.Arg117His variant in the CFTR gene is an established variant for cystic fi brosis (CF) that is recommended for by the American College of … (more) The p.Arg117His variant in the CFTR gene is an established variant for cystic fi brosis (CF) that is recommended for by the American College of Medical Genetics (ACMG) for inclusion on the CF population carrier screening panel (Watson 2004, Moskowitz 2008, Castellani 2008). Functional studies have shown that the p.Arg11 7His variant results in defective protein conductance but retains some residual CFTR function (De Boek 2014). As a result, this variant has been classified as a class IV variant. The severity of lung disease in individuals that are compound heterozygous or homozygous for p.Arg117His variant is contingent on the presenc e of a variation in the poly T/poly TG tract of intron 8 that is in cis (same ch romosome copy) with p.Arg117His. A shorter poly T tract together with a longer T G tract results in the strongest aberrant impact to intron 8 splicing and theref ore associated with more severe disease (Moskowitz 2008). Therefore, individuals with a pathogenic CF variant on one chromosome copy and a 5T variant in cis wit h the p.Arg117His variant on the other chromosome copy usually develop CF-relate d lung disease. In contrast, those with p.Arg117His variant in cis with 7T or 9T variant have a highly variable phenotype that can range from clinically asympto matic to congenital absence of the vas deferens (CAVD) in males and/or non-class ic CF (Kieswetter 1993, Massie 2001). In summary, this variant is classified as pathogenic for CF and related disorders in an autosomal recessive manner. ACMG/A MP criteria applied: PM3_VeryStrong, PS3_Moderate. (less) Number of individuals with the variant: 1
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163473.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020
Pathogenic (May 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: no Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV001251861.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Pathogenic (May 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: no Allele origin: germline	Pars Genome Lab Accession: SCV001736825.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Sex: mixed
Pathogenic (Jul 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001810343.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Sex: mixed
Likely pathogenic (Mar 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501159.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (53): PubMed: 2344617 23420618 31036917 21228398 25797027 7692051 21594800 31589614 18456578 10103316 24440181 21507732 18078365 20797923 20021716 22332135 23751316 22366207 31980526 30279124 7506096 15775704 22572128 25033378 22975760 18394117 31199594 11491164 23951356 12767731 19885835 31213628 20923678 22658665 11484207 27171515 16266832 32429104 20619026 26324139 18778819 17015492 7680769 23974870 21520337 19880712 23378603 23891399 15246977 14618962 27364092 26846474 31447099 Number of individuals with the variant: 2 Secondary finding: no
Pathogenic (Jul 22, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV002523164.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Number of individuals with the variant: 1 Clinical Features: Apneic episodes in infancy (present) , Feeding difficulties (present) , Widely spaced teeth (present) , Sensory neuropathy (present) , Dysarthria (present) , Areflexia (present) , … (more) Apneic episodes in infancy (present) , Feeding difficulties (present) , Widely spaced teeth (present) , Sensory neuropathy (present) , Dysarthria (present) , Areflexia (present) , Dysmetria (present) , Gait ataxia (present) , Dysdiadochokinesis (present) , Truncal ataxia (present) , Broad-based gait (present) , Positive Romberg sign (present) , Upper limb postural tremor (present) , Titubation (present) (less) Age: 10-19 years Sex: female
Pathogenic (Feb 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581402.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4, PM3_STR, PP3, PP4	Number of individuals with the variant: 2 Sex: male
Pathogenic (Nov 05, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: unknown	Mendelics Accession: SCV000886267.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009129.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Jan 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001523284.2 First in ClinVar: Mar 22, 2021 Last updated: Mar 11, 2023
Pathogenic (Jan 09, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000888088.4 First in ClinVar: Mar 13, 2019 Last updated: Jan 06, 2024	Publications: PubMed (58): PubMed: 10103316 11484207 11491164 12767731 14618962 15246977 15775704 16266832 17015492 18078365 18394117 18778819 19885835 20021716 20619026 20797923 20923678 21228398 21507732 21520337 21594800 22332135 22366207 22658665 22975760 23378603 2344617 23751316 23951356 23974870 25797027 26324139 26846474 27171515 30279124 31036917 31199594 31213628 31447099 31589614 31980526 32429104 7680769 34426522 23891399 24440181 23420618 7506096 25033378 11746017 18456578 7692051 22572128 19880712 9435322 11280952 28419121 27364092 Comment: The c.350G>A (p.Arg117His) CFTR pathogenic variant causes the synthesis of a partially functional CFTR protein and is associated with variable expressivity. When this variant occurs … (more) The c.350G>A (p.Arg117His) CFTR pathogenic variant causes the synthesis of a partially functional CFTR protein and is associated with variable expressivity. When this variant occurs on the same chromosome (in cis) with the 7T or 9T polymorphism in intron 9 and with another CFTR pathogenic variant associated with cystic fibrosis (CF) on the opposite chromosome (in trans), it is associated with a variable phenotype. The variable phenotype ranges from asymptomatic to CFTR-related disorders, such as congenital bilateral absence of the vas deferens (CBAVD) in males. However, if the c.350G>A (p.Arg117His) CFTR pathogenic variant occurs in cis with the 5T polymorphism in intron 9 and with a CF pathogenic variant in trans, it is associated with CF (PMID: 32404922 (2020)). (less)
Pathogenic (Jul 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019226.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Uncertain significance (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000074930.12 First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024	Publications: PubMed (12) PubMed: 28492532‚ 7506096‚ 11491164‚ 7691356‚ 7684641‚ 10556281‚ 14685937‚ 21658649‚ 21507732‚ 23974870‚ 19880712‚ 11242048 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 117 of the CFTR protein (p.Arg117His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 117 of the CFTR protein (p.Arg117His). This variant is present in population databases (rs78655421, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense variant (also known as R117H) frequently occurs on the same chromosome as a pathogenic CFTR allele known as IVS8-5T (PMID: 7506096, 11491164). The 5T refers to a polymorphic region in the intron preceding the acceptor splice site for exon 10 (formerly called exon 9). The 5T allele has been demonstrated to result in aberrant mRNA splicing and a non-functional protein, while more common 7T and 9T alleles do not impact splicing and are considered benign (PMID: 7691356, 7684641, 10556281, 14685937, 21658649). Importantly, when R117H is on the same chromosome as the 5T, it may increase the severity of CFTR-related symptoms (PMID: 7506096, 11491164). When on the same chromosome as a 7T or 9T, the R117H variant is not typically associated with cystic fibrosis but may contribute to CFTR-related conditions (PMID: 21507732, 7506096, 23974870). The R117H and T7 (R117H-T7) allele has been reported to be homozygous in a male with congenital absence of vas deferens (CAVD) (PMID: 21507732). This male also had slightly above normal sweat chloride levels (34 mmol/L) but was otherwise asymptomatic for CFTR-related symptoms. In addition, 81 males with R117H-T7 and Phe508del on opposite alleles have been observed to have CAVD, although it has been estimated that only a small percentage (3%) of males in the population with this genotype are affected (PMID: 19880712). ClinVar contains an entry for this variant (Variation ID: 7109). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. The experimental evidence for the R117H-T7 is conflicting. In a heterologous model system, this missense change decreased CFTR activity by ~20-30% (PMID: 11242048), while in airway epithelium cells taken from two individuals homozygous for R117H-T7, chloride conductance levels were normal (PMID: 21507732). In summary, this R117H missense variant may modify disease severity when it occurs on the same chromosome as a 5T allele. When present on the same chromosome as a 7T or 9T allele, the R117H variant does not typically contribute to cystic fibrosis but may contribute to CFTR-related conditions. However, much of the functional and clinical data for the R117H-T7 allele is conflicting. Until this can be resolved, the R117H missense change has been classified as a Variant of Uncertain Significance. (less)
Pathogenic (Nov 13, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602967.8 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Comment: The CFTR c.350G>A; p.Arg117His (R117H) variant (rs78655421) is reported in gene-specific databases (CFTR2 Database, ABCC7 Database and references therein) and ClinVar (Variation ID: 7109). Functional … (more) The CFTR c.350G>A; p.Arg117His (R117H) variant (rs78655421) is reported in gene-specific databases (CFTR2 Database, ABCC7 Database and references therein) and ClinVar (Variation ID: 7109). Functional analyses show that p.Arg117His protein has reduced conductance and a decreased occupancy in the open state (LaRusch 2014, Van Goor 2014, Yu 2016), and this variant is found in the general population at an overall allele frequency of 0.1% (398/276670 alleles, 1 homozygote) in the Genome Aggregation Database. The p.Arg117His variant is associated with two haplotypes of differing phenotypes when identified with a pathogenic variant on the opposite chromosome. When p.Arg117H is on the same chromosome as the 5T variant in IVS 8, this complex variant is considered pathogenic for cystic fibrosis, but in the absence of 5T, p.Arg117His alone is considered mildly pathogenic and associated with CFTR-related disorders, such as an isolated presentation of congenital bilateral absence of the vas deferens or pancreatitis or mild lung disease (Kiesewetter 1993, Raraigh 2022). References: CFTR2 database: http://cftr2.org/ ABCC7 database: http://abcmutations.hegelab.org/mutationDetails?id=4117 Kiesewetter S et al. A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet. 1993 Nov;5(3):274-8. PMID: 7506096. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014 Jul 17;10(7):e1004376. PMID: 25033378. Raraigh KS et al. Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. J Cyst Fibros. 2022 May;21(3):463-470. PMID: 34782259. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36. PMID: 23891399. Yu YC et al. On the mechanism of gating defects caused by the R117H mutation in cystic fibrosis transmembrane conductance regulator. J Physiol. 2016 Jun 15;594(12):3227-44. PMID: 26846474. (less)
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pseudomonas aeruginosa, susceptibility to chronic infection by, in cystic fibrosis Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005016539.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024
Pathogenic (Jan 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714830.3 First in ClinVar: Jun 15, 2021 Last updated: Jun 09, 2024	Other databases https://cftr2.org/mutation/scien… https://cftr2.org/mutation/scientific/R117H/ Number of individuals with the variant: 65
Pathogenic (Sep 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002573882.2 First in ClinVar: Sep 24, 2022 Last updated: Oct 13, 2024	Comment: Criteria applied: PS3,PM3_STR,PM5_STR,PP3; Identified as compund heterozygous with NM_000492.4:c.1521_1523del Clinical Features: Decreased stool elastase level (present) , Increased circulating trypsinogen (present) , Steatorrhea (present) Sex: male
Pathogenic (Apr 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250499.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: CFTR: PM3:Very Strong, PM5, PM2:Supporting, PS3:Supporting Number of individuals with the variant: 7
Likely pathogenic (Nov 04, 2014)	criteria provided, single submitter (HA_assertions_20150911) Method: research	Cystic fibrosis Affected status: unknown Allele origin: unknown, maternal, paternal	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-HudsonAlpha Accession: SCV000584076.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1 Observation 3: Number of individuals with the variant: 1 Observation 4: Number of individuals with the variant: 1 Observation 5: Number of individuals with the variant: 1
Pathogenic (Apr 11, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696973.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (27) PubMed: 10341008‚ 7692051‚ 12767731‚ 7599637‚ 7522329‚ 10653141‚ 9259197‚ 7573058‚ 8698344‚ 15246977‚ 11737931‚ 17015492‚ 7506096‚ 19092437‚ 9272157‚ 7680769‚ 9557894‚ 9950763‚ 9259194‚ 10103316‚ 11168024‚ 1283148‚ 10909845‚ 8825927‚ 7544788‚ 23974870‚ 9550361 Comment: Variant summary: The variant of interest causes a missense change involving a conserved nucleotide with 5/5 in silico programs predicting a "deleterious" outcome. The variant … (more) Variant summary: The variant of interest causes a missense change involving a conserved nucleotide with 5/5 in silico programs predicting a "deleterious" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 185/120360 (1/650), which does not exceed the predicted maximum expected allele frequency for a pathogenic CFTR variant of 1/100. The variant of interest has been reported in multiple affected individuals via publications and databases that indicate that the variant of interest is a common disease variant with varying severity dependent on additional CFTR variants in cis and trans. Functional studies indicate that the variant of interest impedes wild type function. In addition, multiple reputable clinical laboratories cite the variant with a classification of "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. (less)
Pathogenic (Jan 29, 2018)	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017)) Method: curation	CFTR-related disorders Affected status: yes, no Allele origin: germline	CFTR-France Accession: SCV001169573.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918 Observation 1: Sex: mixed Observation 2: Sex: female
Pathogenic (Oct 18, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193802.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (2) PubMed: 23974870‚ 15371902 Comment: NM_000492.3(CFTR):c.350G>A(R117H) is classified as pathogenic in the context of cystic fibrosis. Please note that the R117H mutation is associated with a broad spectrum of disease, … (more) NM_000492.3(CFTR):c.350G>A(R117H) is classified as pathogenic in the context of cystic fibrosis. Please note that the R117H mutation is associated with a broad spectrum of disease, ranging from clinically asymptomatic to CAVD/non-classic cystic fibrosis. Individuals with R117H should have testing for the poly-T tract (5T) to determine accurate risk. Individuals with R117H and 5T in cis are at highest risk for CF symptoms. In the absence of the 5T haplotype, the R117H mutation is unlikely to produce significant symptoms of cystic fibrosis. The R117H mutation in combination with another disease causing mutation may result in borderline or elevated sweat chloride and mild clinical symptoms of CF, including male infertility. Sources used for classification include PMID 23974870 and 15371902. In summary, classification of NM_000492.3(CFTR):c.350G>A(R117H) is based on the following criteria: high frequency variant with variable penetrance and variable severity dependent on the presence of other variants in the gene. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446979.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Azoospermia (present) Sex: male
Pathogenic (Aug 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Obstructive azoospermia Affected status: yes Allele origin: germline	Institute of Reproductive Genetics, University of Münster Accession: SCV001860326.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Number of individuals with the variant: 4
Pathogenic (Jul 23, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002507318.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022
Pathogenic (Apr 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893738.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Oct 07, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001181971.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 23378603‚ 26846474‚ 27469177 Comment: The p.R117H pathogenic mutation (also known as c.350G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at … (more) The p.R117H pathogenic mutation (also known as c.350G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 350. The arginine at codon 117 is replaced by histidine, an amino acid with highly similar properties. The penetrance of the p.R117H mutation is modified by the poly-thymidine tract in CFTR intron 9; decreasing length of the poly-thymidine tract correlates with an increased risk for cystic fibrosis phenotype. When p.R117H is on the same chromosome as 5T (in cis) it is a disease causing mutation; when in cis with 7T, the allele acts as a variant of varying clinical consequence (VVCC) (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7; Sosnay PR et al. Pediatr. Clin. North Am. 2016 Aug;63(4):585-98). In a study of 179 individuals who were compound heterozygous for p.R117H and another pathogenic CFTR mutation, 172 had poly-thymidine variant results documented, with the majority being 7T and only five individuals carrying the 5T allele. Clinical data were available for 166 individuals and diagnoses included: isolated CBAVD (83 individuals), CFTR-related disorder with mild or absent pulmonary disease (67 individuals), late-onset marked pulmonary disease (4 individuals), and asymptomatic (12 individuals) (Thauvin-Robinet C et al. J. Med. Genet., 2013 Apr;50:220-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bronchiectasis with or without elevated sweat chloride 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004211622.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197448.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Nov 01, 2009)	no assertion criteria provided Method: literature only	CYSTIC FIBROSIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027729.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 26, 2017	Publications: PubMed (7) PubMed: 1937486‚ 8421472‚ 7692051‚ 7506096‚ 2349952‚ 11746017‚ 19880712 Comment on evidence: In 2 presumably unrelated families with mild cystic fibrosis (CF; 219700), Dean et al. (1990) found a 482G-A transition in exon 4 of the CFTR … (more) In 2 presumably unrelated families with mild cystic fibrosis (CF; 219700), Dean et al. (1990) found a 482G-A transition in exon 4 of the CFTR gene, resulting in an arg117-to-his (R117H) substitution. Gervais et al. (1993) reported that the R117H mutation was present in 4 of 23 patients with congenital absence of the vas deferens (CBAVD; 277180). Three patients had compound heterozygosity for R117H and delF508 (602421.0001), whereas a fourth was a compound heterozygote for R117H and 2322delG. None of the 23 patients had pulmonary evidence of cystic fibrosis. Five patients without the delF508 mutation had unilateral renal agenesis in addition to absence of the vas deferens; these patients may represent a different distinct subset. Bienvenu et al. (1993) described for the first time homozygosity for the R117H mutation in a 30-year-old French male with sterility owing to congenital bilateral absence of the vas deferens. The subject had no respiratory or pancreatic involvement and had a normal sweat electrolyte value. His parents were not consanguineous, and there were no other cases of CBAVD or CF in the family. Kiesewetter et al. (1993) presented evidence that the chromosome background of the R117H mutation has a profound effect on the phenotype produced. Three length variants of CFTR have been observed with varying degrees of exon 9 splicing depending on variation in the length of the polypyrimidine tract in the splice acceptor site in intron 8 (Chu et al., 1991, 1993). Varied lengths of a thymidine (T)-tract (5, 7, or 9Ts) were noted in front of the splice acceptor site of intron 8. The 5T variant is present in 5% of the CFTR alleles among Caucasian populations producing almost exclusively (95%) exon 9-minus RNA. The effect of this T-tract polymorphism in CFTR gene expression was also documented by its relationship with the R117H mutation: R117H (5T) is found in typical CF patients with pancreatic sufficiency; R117H (7T) is associated with CBAVD. The R117H mutation has been reported in CF patients, males with congenital bilateral absence of the vas deferens, and in an asymptomatic woman. Furthermore, population screening discovered a 19-fold higher than expected number of carriers of this CF mutation. The situation was compared to that in Gaucher disease in which the severity of neuronopathic disease associated with a missense mutation appears to be altered by additional missense mutations in the same allele (Latham et al., 1990). White et al. (2001) reported a healthy 29-year-old female who was found to be an R117H/delF508 heterozygote. The patient had atopic asthma and infertility, but normal height and weight and no pulmonary symptoms of CF. Analysis of the polythymidine tract showed that the R117H mutation was in cis with a 7T tract and the delta-F508 mutation in cis with a 9T tract. The authors concluded that poly-T studies are important in any patient found to have the R117H mutation, and recommended caution in the genetic counseling of such families. Thauvin-Robinet et al. (2009) reported the results of a national collaborative study in France to establish the overall phenotype associated with R117H and to evaluate the disease penetrance of the R117H+F508del genotype. In 184 R117H+F508del individuals of the French population, including 72 newborns, the disease phenotype was predominantly mild; 1 child had classic cystic fibrosis, and 3 adults had severe pulmonary symptoms. In 5,245 healthy adults with no family history of CF, the allelic prevalence of F508del was 1.06%, R117H;T7 0.27%, and R117H;T5 less than 0.01%. The theoretical number of R117H;T7+F508del individuals in the French populations was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classic CF for R117H;T7+F508del was estimated at 0.03% and that of severe CF in adulthood at 0.06%. Thauvin-Robinet et al. (2009) suggested that R117H should be withdrawn from CF mutation panels used for screening programs. (less)
Pathogenic (Nov 01, 2009)	no assertion criteria provided Method: literature only	VAS DEFERENS, CONGENITAL BILATERAL ABSENCE OF Affected status: not provided Allele origin: germline	OMIM Accession: SCV000053488.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 12, 2018	Publications: PubMed (7) PubMed: 1937486‚ 8421472‚ 7692051‚ 7506096‚ 2349952‚ 11746017‚ 19880712 Comment on evidence: In 2 presumably unrelated families with mild cystic fibrosis (CF; 219700), Dean et al. (1990) found a 482G-A transition in exon 4 of the CFTR … (more) In 2 presumably unrelated families with mild cystic fibrosis (CF; 219700), Dean et al. (1990) found a 482G-A transition in exon 4 of the CFTR gene, resulting in an arg117-to-his (R117H) substitution. Gervais et al. (1993) reported that the R117H mutation was present in 4 of 23 patients with congenital absence of the vas deferens (CBAVD; 277180). Three patients had compound heterozygosity for R117H and delF508 (602421.0001), whereas a fourth was a compound heterozygote for R117H and 2322delG. None of the 23 patients had pulmonary evidence of cystic fibrosis. Five patients without the delF508 mutation had unilateral renal agenesis in addition to absence of the vas deferens; these patients may represent a different distinct subset. Bienvenu et al. (1993) described for the first time homozygosity for the R117H mutation in a 30-year-old French male with sterility owing to congenital bilateral absence of the vas deferens. The subject had no respiratory or pancreatic involvement and had a normal sweat electrolyte value. His parents were not consanguineous, and there were no other cases of CBAVD or CF in the family. Kiesewetter et al. (1993) presented evidence that the chromosome background of the R117H mutation has a profound effect on the phenotype produced. Three length variants of CFTR have been observed with varying degrees of exon 9 splicing depending on variation in the length of the polypyrimidine tract in the splice acceptor site in intron 8 (Chu et al., 1991, 1993). Varied lengths of a thymidine (T)-tract (5, 7, or 9Ts) were noted in front of the splice acceptor site of intron 8. The 5T variant is present in 5% of the CFTR alleles among Caucasian populations producing almost exclusively (95%) exon 9-minus RNA. The effect of this T-tract polymorphism in CFTR gene expression was also documented by its relationship with the R117H mutation: R117H (5T) is found in typical CF patients with pancreatic sufficiency; R117H (7T) is associated with CBAVD. The R117H mutation has been reported in CF patients, males with congenital bilateral absence of the vas deferens, and in an asymptomatic woman. Furthermore, population screening discovered a 19-fold higher than expected number of carriers of this CF mutation. The situation was compared to that in Gaucher disease in which the severity of neuronopathic disease associated with a missense mutation appears to be altered by additional missense mutations in the same allele (Latham et al., 1990). White et al. (2001) reported a healthy 29-year-old female who was found to be an R117H/delF508 heterozygote. The patient had atopic asthma and infertility, but normal height and weight and no pulmonary symptoms of CF. Analysis of the polythymidine tract showed that the R117H mutation was in cis with a 7T tract and the delta-F508 mutation in cis with a 9T tract. The authors concluded that poly-T studies are important in any patient found to have the R117H mutation, and recommended caution in the genetic counseling of such families. Thauvin-Robinet et al. (2009) reported the results of a national collaborative study in France to establish the overall phenotype associated with R117H and to evaluate the disease penetrance of the R117H+F508del genotype. In 184 R117H+F508del individuals of the French population, including 72 newborns, the disease phenotype was predominantly mild; 1 child had classic cystic fibrosis, and 3 adults had severe pulmonary symptoms. In 5,245 healthy adults with no family history of CF, the allelic prevalence of F508del was 1.06%, R117H;T7 0.27%, and R117H;T5 less than 0.01%. The theoretical number of R117H;T7+F508del individuals in the French populations was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classic CF for R117H;T7+F508del was estimated at 0.03% and that of severe CF in adulthood at 0.06%. Thauvin-Robinet et al. (2009) suggested that R117H should be withdrawn from CF mutation panels used for screening programs. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001550195.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The CFTR p.R117H variant has been reported in the literature as a common variant known to be associated with Cystic Fibrosis (CF) and CF-related diseases, … (more) The CFTR p.R117H variant has been reported in the literature as a common variant known to be associated with Cystic Fibrosis (CF) and CF-related diseases, however the phenotype may range from asymptomatic to the classical CF phenotype (Thauvin-Robinet_2013_PMID:23378603; De-Nooijer_2011_PMID:21507732; Thauvin-Robinet_2009_PMID:19880712; Ong_2001_PMID:20301428; White_2001_PMID:11746017; Massie_2001_PMID:11491164; Dasouki_1998_PMID:9557894). The severity of the p.R117H variant has been reported to depend on variation of the poly T tract in intron 9 of the CFTR gene. When the p.R117H variant is found in cis with the 5T variant individuals typically display a more severe phenotype, while individuals with the p.R117H variant and the 7T or 9T variants may have a mild or aymptomatic phenotype (Massie_2001_PMID:11491164; Chmiel_1999_PMID:10103316; Kieswetter_1993_PMID:7506096).Â¬â€ The variant was identified in dbSNP (ID: rs78655421) and ClinVar (classified as pathogenic by Ambry Genetics, Laboratory for Molecular Medicine and 17 other submitters; as likely pathogenic by Hudson Alpha Institute for Biotechnology; as uncertain significance by Invitae; and as 'drug response' by PharmGKB). The variant was identified in control databases in 406 of 282346 chromosomes (1 homozygous) at a frequency of 0.001438, and was observed at the highest frequency in the European (non-Finnish) population in 323 of 128902 chromosomes (1 homozygous) (freq: 0.002506) (Genome Aggregation Database March 6, 2019, v2.1.1). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. The p.R117 residue is conserved in mammals and more distantly related organisms, and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein. Functional evidence indicates that the p.R117H variant causes gating defects in CFTR function and results in reduced channel conductance, but retains some residual activity (Yu_2016_PMID:26846474). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less)
Pathogenic (Jul 23, 2019)	no assertion criteria provided Method: clinical testing	CFTR-related disorders Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002507402.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022
not provided (-)	no classification provided Method: literature only	Cystic fibrosis Affected status: unknown Allele origin: unknown	GeneReviews Accession: SCV001622784.2 First in ClinVar: May 23, 2021 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 20301428‚ 15371902 BookShelf: NBK1250 BookShelf: NBK1250
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Comment:

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.

Comment:

The R117H variant in the CFTR gene has been reported multiple times previously as a common variant in the CFTR gene (Moskowitz et al., 2008). R117H is a class IV variant which results in defective protein conductance but allows for some residual CFTR function (De Boeck et al., 2014). The severity of disease in individuals with one or two R117H pathogenic variants depends on the presence of a variation in the intron 8 poly T tract and the length of the TG tract in cis configuration with the R117H variant (Moskowitz et al., 2008). A longer TG tract in association with a shorter poly T tract has the strongest adverse effect on intron 8 splicing and are associated with more severe disease (Moskowitz et al., 2008). Individuals with a CFTR pathogenic variant in trans with the R117H variant and 5T variant usually develop the lung disease of CF, but individuals with R117H and the 7T variant or the 9T variant have a highly variable phenotype ranging from clinically asymptomatic to congenital absence of the vas deferens (CAVD) and/or non-classic cystic fibrosis (Moskowitz et al., 2008). Given the available information, we interpret R117H as a pathogenic variant.

Comment:

The CFTR c.350G>A (p.Arg117His) variant is included within the American College of Medical Genetics and Genomics (ACMG) recommended carrier screening panel for cystic fibrosis (Grody et al. 2001). There are multiple clinical implications for the p.Arg117His variant that are dependent on the length of the intron 8 polythymidine tract (polyT) region within the CFTR gene. Kiesewetter et al. (1993) and Massie et al. (2001) assessed the influence of the intron-8 polythymidine sequence (IVS8) on the relationship between the genotype and phenotype of individuals with the p.Arg117His variant. They found that when the p.Arg117His variant was found in cis with five thymidines (5T), and in trans to a pathogenic CF variant, the individual was most commonly affected with classic CF. When the p.Arg117His variant was identified in cis with seven thymidines (7T) and in trans to a pathogenic CF variant, male individuals were often affected with congenital absence of the vas deferens (CAVD), and males and females often presented with a milder variation of CF. In the CFTR2 database, the variant was found in 793 CF patients (808 alleles) and was classified as a mutation of varying clinical consequence (Sosnay et al. 2013). The p.Arg117His variant is reported at a frequency of 0.00256 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Arg117His variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

The p.Arg117His variant in the CFTR gene is an established variant for cystic fi brosis (CF) that is recommended for by the American College of Medical Genetics (ACMG) for inclusion on the CF population carrier screening panel (Watson 2004, Moskowitz 2008, Castellani 2008). Functional studies have shown that the p.Arg11 7His variant results in defective protein conductance but retains some residual CFTR function (De Boek 2014). As a result, this variant has been classified as a class IV variant. The severity of lung disease in individuals that are compound heterozygous or homozygous for p.Arg117His variant is contingent on the presenc e of a variation in the poly T/poly TG tract of intron 8 that is in cis (same ch romosome copy) with p.Arg117His. A shorter poly T tract together with a longer T G tract results in the strongest aberrant impact to intron 8 splicing and theref ore associated with more severe disease (Moskowitz 2008). Therefore, individuals with a pathogenic CF variant on one chromosome copy and a 5T variant in cis wit h the p.Arg117His variant on the other chromosome copy usually develop CF-relate d lung disease. In contrast, those with p.Arg117His variant in cis with 7T or 9T variant have a highly variable phenotype that can range from clinically asympto matic to congenital absence of the vas deferens (CAVD) in males and/or non-class ic CF (Kieswetter 1993, Massie 2001). In summary, this variant is classified as pathogenic for CF and related disorders in an autosomal recessive manner. ACMG/A MP criteria applied: PM3_VeryStrong, PS3_Moderate.

Comment:

The c.350G>A (p.Arg117His) CFTR pathogenic variant causes the synthesis of a partially functional CFTR protein and is associated with variable expressivity. When this variant occurs on the same chromosome (in cis) with the 7T or 9T polymorphism in intron 9 and with another CFTR pathogenic variant associated with cystic fibrosis (CF) on the opposite chromosome (in trans), it is associated with a variable phenotype. The variable phenotype ranges from asymptomatic to CFTR-related disorders, such as congenital bilateral absence of the vas deferens (CBAVD) in males. However, if the c.350G>A (p.Arg117His) CFTR pathogenic variant occurs in cis with the 5T polymorphism in intron 9 and with a CF pathogenic variant in trans, it is associated with CF (PMID: 32404922 (2020)).

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 117 of the CFTR protein (p.Arg117His). This variant is present in population databases (rs78655421, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense variant (also known as R117H) frequently occurs on the same chromosome as a pathogenic CFTR allele known as IVS8-5T (PMID: 7506096, 11491164). The 5T refers to a polymorphic region in the intron preceding the acceptor splice site for exon 10 (formerly called exon 9). The 5T allele has been demonstrated to result in aberrant mRNA splicing and a non-functional protein, while more common 7T and 9T alleles do not impact splicing and are considered benign (PMID: 7691356, 7684641, 10556281, 14685937, 21658649). Importantly, when R117H is on the same chromosome as the 5T, it may increase the severity of CFTR-related symptoms (PMID: 7506096, 11491164). When on the same chromosome as a 7T or 9T, the R117H variant is not typically associated with cystic fibrosis but may contribute to CFTR-related conditions (PMID: 21507732, 7506096, 23974870). The R117H and T7 (R117H-T7) allele has been reported to be homozygous in a male with congenital absence of vas deferens (CAVD) (PMID: 21507732). This male also had slightly above normal sweat chloride levels (34 mmol/L) but was otherwise asymptomatic for CFTR-related symptoms. In addition, 81 males with R117H-T7 and Phe508del on opposite alleles have been observed to have CAVD, although it has been estimated that only a small percentage (3%) of males in the population with this genotype are affected (PMID: 19880712). ClinVar contains an entry for this variant (Variation ID: 7109). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. The experimental evidence for the R117H-T7 is conflicting. In a heterologous model system, this missense change decreased CFTR activity by ~20-30% (PMID: 11242048), while in airway epithelium cells taken from two individuals homozygous for R117H-T7, chloride conductance levels were normal (PMID: 21507732). In summary, this R117H missense variant may modify disease severity when it occurs on the same chromosome as a 5T allele. When present on the same chromosome as a 7T or 9T allele, the R117H variant does not typically contribute to cystic fibrosis but may contribute to CFTR-related conditions. However, much of the functional and clinical data for the R117H-T7 allele is conflicting. Until this can be resolved, the R117H missense change has been classified as a Variant of Uncertain Significance.

Comment:

The CFTR c.350G>A; p.Arg117His (R117H) variant (rs78655421) is reported in gene-specific databases (CFTR2 Database, ABCC7 Database and references therein) and ClinVar (Variation ID: 7109). Functional analyses show that p.Arg117His protein has reduced conductance and a decreased occupancy in the open state (LaRusch 2014, Van Goor 2014, Yu 2016), and this variant is found in the general population at an overall allele frequency of 0.1% (398/276670 alleles, 1 homozygote) in the Genome Aggregation Database. The p.Arg117His variant is associated with two haplotypes of differing phenotypes when identified with a pathogenic variant on the opposite chromosome. When p.Arg117H is on the same chromosome as the 5T variant in IVS 8, this complex variant is considered pathogenic for cystic fibrosis, but in the absence of 5T, p.Arg117His alone is considered mildly pathogenic and associated with CFTR-related disorders, such as an isolated presentation of congenital bilateral absence of the vas deferens or pancreatitis or mild lung disease (Kiesewetter 1993, Raraigh 2022). References: CFTR2 database: http://cftr2.org/ ABCC7 database: http://abcmutations.hegelab.org/mutationDetails?id=4117 Kiesewetter S et al. A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet. 1993 Nov;5(3):274-8. PMID: 7506096. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014 Jul 17;10(7):e1004376. PMID: 25033378. Raraigh KS et al. Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment. J Cyst Fibros. 2022 May;21(3):463-470. PMID: 34782259. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36. PMID: 23891399. Yu YC et al. On the mechanism of gating defects caused by the R117H mutation in cystic fibrosis transmembrane conductance regulator. J Physiol. 2016 Jun 15;594(12):3227-44. PMID: 26846474.

Comment:

Variant summary: The variant of interest causes a missense change involving a conserved nucleotide with 5/5 in silico programs predicting a "deleterious" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 185/120360 (1/650), which does not exceed the predicted maximum expected allele frequency for a pathogenic CFTR variant of 1/100. The variant of interest has been reported in multiple affected individuals via publications and databases that indicate that the variant of interest is a common disease variant with varying severity dependent on additional CFTR variants in cis and trans. Functional studies indicate that the variant of interest impedes wild type function. In addition, multiple reputable clinical laboratories cite the variant with a classification of "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.

Comment:

NM_000492.3(CFTR):c.350G>A(R117H) is classified as pathogenic in the context of cystic fibrosis. Please note that the R117H mutation is associated with a broad spectrum of disease, ranging from clinically asymptomatic to CAVD/non-classic cystic fibrosis. Individuals with R117H should have testing for the poly-T tract (5T) to determine accurate risk. Individuals with R117H and 5T in cis are at highest risk for CF symptoms. In the absence of the 5T haplotype, the R117H mutation is unlikely to produce significant symptoms of cystic fibrosis. The R117H mutation in combination with another disease causing mutation may result in borderline or elevated sweat chloride and mild clinical symptoms of CF, including male infertility. Sources used for classification include PMID 23974870 and 15371902. In summary, classification of NM_000492.3(CFTR):c.350G>A(R117H) is based on the following criteria: high frequency variant with variable penetrance and variable severity dependent on the presence of other variants in the gene. Please note: this variant was assessed in the context of healthy population screening.

Comment:

The p.R117H pathogenic mutation (also known as c.350G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 350. The arginine at codon 117 is replaced by histidine, an amino acid with highly similar properties. The penetrance of the p.R117H mutation is modified by the poly-thymidine tract in CFTR intron 9; decreasing length of the poly-thymidine tract correlates with an increased risk for cystic fibrosis phenotype. When p.R117H is on the same chromosome as 5T (in cis) it is a disease causing mutation; when in cis with 7T, the allele acts as a variant of varying clinical consequence (VVCC) (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7; Sosnay PR et al. Pediatr. Clin. North Am. 2016 Aug;63(4):585-98). In a study of 179 individuals who were compound heterozygous for p.R117H and another pathogenic CFTR mutation, 172 had poly-thymidine variant results documented, with the majority being 7T and only five individuals carrying the 5T allele. Clinical data were available for 166 individuals and diagnoses included: isolated CBAVD (83 individuals), CFTR-related disorder with mild or absent pulmonary disease (67 individuals), late-onset marked pulmonary disease (4 individuals), and asymptomatic (12 individuals) (Thauvin-Robinet C et al. J. Med. Genet., 2013 Apr;50:220-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

The CFTR p.R117H variant has been reported in the literature as a common variant known to be associated with Cystic Fibrosis (CF) and CF-related diseases, however the phenotype may range from asymptomatic to the classical CF phenotype (Thauvin-Robinet_2013_PMID:23378603; De-Nooijer_2011_PMID:21507732; Thauvin-Robinet_2009_PMID:19880712; Ong_2001_PMID:20301428; White_2001_PMID:11746017; Massie_2001_PMID:11491164; Dasouki_1998_PMID:9557894). The severity of the p.R117H variant has been reported to depend on variation of the poly T tract in intron 9 of the CFTR gene. When the p.R117H variant is found in cis with the 5T variant individuals typically display a more severe phenotype, while individuals with the p.R117H variant and the 7T or 9T variants may have a mild or aymptomatic phenotype (Massie_2001_PMID:11491164; Chmiel_1999_PMID:10103316; Kieswetter_1993_PMID:7506096).Â¬â€ The variant was identified in dbSNP (ID: rs78655421) and ClinVar (classified as pathogenic by Ambry Genetics, Laboratory for Molecular Medicine and 17 other submitters; as likely pathogenic by Hudson Alpha Institute for Biotechnology; as uncertain significance by Invitae; and as 'drug response' by PharmGKB). The variant was identified in control databases in 406 of 282346 chromosomes (1 homozygous) at a frequency of 0.001438, and was observed at the highest frequency in the European (non-Finnish) population in 323 of 128902 chromosomes (1 homozygous) (freq: 0.002506) (Genome Aggregation Database March 6, 2019, v2.1.1). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. The p.R117 residue is conserved in mammals and more distantly related organisms, and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein. Functional evidence indicates that the p.R117H variant causes gating defects in CFTR function and results in reduced channel conductance, but retains some residual activity (Yu_2016_PMID:26846474). In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients.	Petrova NV	Genes	2020	PMID: 32429104
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: agibbs@bcm.edu	American journal of human genetics	2019	PMID: 31447099
Severe pulmonary disease in an adult primary ciliary dyskinesia population in Brazil.	Olm MAK	Scientific reports	2019	PMID: 31213628
Identification of a novel large deletion and other copy number variations in the CFTR gene in patients with Cystic Fibrosis from a multiethnic population.	Martins RDS	Molecular genetics & genomic medicine	2019	PMID: 31199594
Sequencing as a first-line methodology for cystic fibrosis carrier screening.	Beauchamp KA	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 31036917
Phenotypic spectrum of patients with cystic fibrosis and cystic fibrosis-related disease carrying p.Arg117His.	Keenan K	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2019	PMID: 30279124
The magnitude of ivacaftor effects on fluid secretion via R117H-CFTR channels: Human in vivo measurements.	Char JE	PloS one	2017	PMID: 28419121
Molecular Genetics of Cystic Fibrosis Transmembrane Conductance Regulator: Genotype and Phenotype.	Sosnay PR	Pediatric clinics of North America	2016	PMID: 27469177
Phenotypic variability of R117H-CFTR expression within monozygotic twins.	Waller MD	Paediatric respiratory reviews	2016	PMID: 27364092
Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis.	Palermo JJ	Pancreas	2016	PMID: 27171515
On the mechanism of gating defects caused by the R117H mutation in cystic fibrosis transmembrane conductance regulator.	Yu YC	The Journal of physiology	2016	PMID: 26846474
The Role of Ivacaftor in Severe Cystic Fibrosis in a Patient With the R117H Mutation.	Ronan NJ	Chest	2015	PMID: 26324139
Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial.	Moss RB	The Lancet. Respiratory medicine	2015	PMID: 26070913
Should diffuse bronchiectasis still be considered a CFTR-related disorder?	Bergougnoux A	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2015	PMID: 25797027
Ivacaftor as salvage therapy in a patient with cystic fibrosis genotype F508del/R117H/IVS8-5T.	Carter S	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2015	PMID: 25698453
Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis.	LaRusch J	PLoS genetics	2014	PMID: 25033378
The relative frequency of CFTR mutation classes in European patients with cystic fibrosis.	De Boeck K	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2014	PMID: 24440181
Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function.	Van Goor F	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2014	PMID: 23891399
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients.	Masson E	PloS one	2013	PMID: 23951356
Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants.	Hamoir C	Digestion	2013	PMID: 23751316
Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level.	Aissat A	Human mutation	2013	PMID: 23420618
CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders.	Thauvin-Robinet C	Journal of medical genetics	2013	PMID: 23378603
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.	Lazarin GA	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22975760
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis.	Ooi CY	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2012	PMID: 22658665
Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred.	LaRusch J	JOP : Journal of the pancreas	2012	PMID: 22572128
Pulmonary Mycobacterium abscessus: a canary in the cystic fibrosis coalmine.	Haverkamp MH	The Journal of infection	2012	PMID: 22366207
Cystic fibrosis transmembrane conductance regulator gene abnormalities in patients with asthma and recurrent neutrophilic bronchitis.	Goodwin J	Canadian respiratory journal	2012	PMID: 22332135
Recommendations for the classification of diseases as CFTR-related disorders.	Bombieri C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2011	PMID: 21658649
Application of high-resolution single-channel recording to functional studies of cystic fibrosis mutants.	Cai Z	Methods in molecular biology (Clifton, N.J.)	2011	PMID: 21594800
Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens.	Steiner B	Human mutation	2011	PMID: 21520337
Assessment of CFTR function in homozygous R117H-7T subjects.	de Nooijer RA	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2011	PMID: 21507732
Carrier testing for severe childhood recessive diseases by next-generation sequencing.	Bell CJ	Science translational medicine	2011	PMID: 21228398
Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis.	Ooi CY	Gastroenterology	2011	PMID: 20923678
Mutational spectrum of cystic fibrosis in the Lebanese population.	Farra C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2010	PMID: 20797923
[Cystic fibrosis in a woman aged seventy].	Ras JE	Nederlands tijdschrift voor geneeskunde	2010	PMID: 20619026
Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma.	McWilliams RR	Cancer	2010	PMID: 19885835
Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners.	Gallati S	Reproductive biomedicine online	2009	PMID: 20021716
The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening.	Thauvin-Robinet C	Journal of medical genetics	2009	PMID: 19880712
Clinical and molecular characterization of S1118F-CFTR.	Penmatsa H	Pediatric pulmonology	2009	PMID: 19774621
Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders.	Moskowitz SM	Genetics in medicine : official journal of the American College of Medical Genetics	2008	PMID: 19092437
Infertility and abnormal cervical mucus in two sisters who are compound heterozygotes for the cystic fibrosis (CF) DeltaF508 and R117H/7T mutations.	Schoyer KD	Fertility and sterility	2008	PMID: 18778819
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.	Castellani C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2008	PMID: 18456578
Respiratory exacerbations in childhood associated with compound heterozygosity Phe508del/Arg117His-7T of the cystic fibrosis transmembrane regulator gene.	Lee TW	Acta paediatrica (Oslo, Norway : 1992)	2008	PMID: 18394117
A family with atypical cystic fibrosis: brother and sister with heterozygosity for both G542X and R117H.	Farez-Vidal ME	Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society	2008	PMID: 18078365
Immunoreactive trypsin/DNA newborn screening for cystic fibrosis: should the R117H variant be included in CFTR mutation panels?	Scotet V	Pediatrics	2006	PMID: 17015492
Delayed diagnosis of cystic fibrosis associated with R117H on a background of 7T polythymidine tract at intron 8.	Peckham D	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2006	PMID: 16266832
Relapsing pancreatitis due to a novel compound heterozygosity in the CFTR gene involving the second most common mutation in central and eastern Europe [CFTRdele2,3(21 kb)].	Lamprecht G	Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]	2005	PMID: 15775704
Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.	Watson MS	Genetics in medicine : official journal of the American College of Medical Genetics	2004	PMID: 15371902
Role of Cftr genotype in the response to chronic Pseudomonas aeruginosa lung infection in mice.	van Heeckeren AM	American journal of physiology. Lung cellular and molecular physiology	2004	PMID: 15246977
Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.	Groman JD	American journal of human genetics	2004	PMID: 14685937
Cystic fibrosis: an unusual cause of chronic pancreatitis.	Vanderbruggen K	Acta gastro-enterologica Belgica	2003	PMID: 14618962
Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study.	McKone EF	Lancet (London, England)	2003	PMID: 12767731
Cystic fibrosis: a further case of an asymptomatic compound heterozygote.	White SM	American journal of medical genetics	2001	PMID: 11746017
'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations.	Noone PG	Respiratory research	2001	PMID: 11737931
Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C.	Massie RJ	The European respiratory journal	2001	PMID: 11491164
XV-2c/KM-19 haplotype analysis of cystic fibrosis mutations in Mexican patients.	Orozco L	American journal of medical genetics	2001	PMID: 11484207
Laboratory standards and guidelines for population-based cystic fibrosis carrier screening.	Grody WW	Genetics in medicine : official journal of the American College of Medical Genetics	2001	PMID: 11280952
Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis.	Choi JY	Nature	2001	PMID: 11242048
Prevalence of CFTR mutations in hypertrypsinaemia detected through neonatal screening for cystic fibrosis.	Scotet V	Clinical genetics	2001	PMID: 11168024
Molecular basis of hereditary pancreatitis.	Chen JM	European journal of human genetics : EJHG	2000	PMID: 10909845
Study of mutant and polyvariant mutant CFTR genes in patients with congenital absence of the vas deferens.	Ravnik-Glavac M	Pflugers Archiv : European journal of physiology	2000	PMID: 10653141
Functional analysis of cis-acting elements regulating the alternative splicing of human CFTR exon 9.	Niksic M	Human molecular genetics	1999	PMID: 10556281
Screening for cystic fibrosis transmembrane conductance regulator gene mutations in men included in an intracytoplasmic sperm injection programme.	Boucher D	Molecular human reproduction	1999	PMID: 10341008
Pitfall in the use of genotype analysis as the sole diagnostic criterion for cystic fibrosis.	Chmiel JF	Pediatrics	1999	PMID: 10103316
Adenosine and its nucleotides activate wild-type and R117H CFTR through an A2B receptor-coupled pathway.	Clancy JP	The American journal of physiology	1999	PMID: 9950763
Heterogeneity in hereditary pancreatitis.	Dasouki MJ	American journal of medical genetics	1998	PMID: 9557894
The incidence of cystic fibrosis in Scotland calculated from heterozygote frequencies.	Brock DJ	Clinical genetics	1998	PMID: 9550361
Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation.	Cuppens H	The Journal of clinical investigation	1998	PMID: 9435322
Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens.	Dörk T	Human genetics	1997	PMID: 9272157
Geographic distribution and regional origin of 272 cystic fibrosis mutations in European populations. The Biomed CF Mutation Analysis Consortium.	Estivill X	Human mutation	1997	PMID: 9259197
Rapid characterization of the variable length polythymidine tract in the cystic fibrosis (CFTR) gene: association of the 5T allele with selected CFTR mutations and its incidence in atypical sinopulmonary disease.	Friedman KJ	Human mutation	1997	PMID: 9259194
Frequencies of cystic fibrosis mutations in the Maine population: high proportion of unknown alleles in individuals of French-Canadian ancestry.	Bayleran JK	Human genetics	1996	PMID: 8698344
The Irish cystic fibrosis database.	Cashman SM	Journal of medical genetics	1995	PMID: 8825927
A single-tube multiplex system for the simultaneous detection of 10 common cystic fibrosis mutations.	Axton RA	Human mutation	1995	PMID: 7599637
CFTR gene variant for patients with congenital absence of vas deferens.	Zielenski J	American journal of human genetics	1995	PMID: 7573058
Pyrophosphate stimulates wild-type and mutant cystic fibrosis transmembrane conductance regulator Cl- channels.	Carson MR	The Journal of biological chemistry	1995	PMID: 7544788
Phosphatase inhibitors activate normal and defective CFTR chloride channels.	Becq F	Proceedings of the National Academy of Sciences of the United States of America	1994	PMID: 7522329
High frequency of the R117H cystic fibrosis mutation in patients with congenital absence of the vas deferens.	Gervais R	The New England journal of medicine	1993	PMID: 8421472
Male infertility as the only presenting sign of cystic fibrosis when homozygous for the mild mutation R117H.	Bienvenu T	Journal of medical genetics	1993	PMID: 7692051
Cystic fibrosis transmembrane conductance regulator splice variants are not conserved and fail to produce chloride channels.	Delaney SJ	Nature genetics	1993	PMID: 7691356
Expression of an abundant alternatively spliced form of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is not associated with a cAMP-activated chloride conductance.	Strong TV	Human molecular genetics	1993	PMID: 7684641
Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties.	Sheppard DN	Nature	1993	PMID: 7680769
A mutation in CFTR produces different phenotypes depending on chromosomal background.	Kiesewetter S	Nature genetics	1993	PMID: 7506096
The spectrum of CFTR mutations in south-west German cystic fibrosis patients.	Lindner M	Human genetics	1992	PMID: 1283148
Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada).	De Braekeleer M	Human heredity	1991	PMID: 1937486
Complex alleles of the acid beta-glucosidase gene in Gaucher disease.	Latham T	American journal of human genetics	1990	PMID: 2349952
Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients.	Dean M	Cell	1990	PMID: 2344617
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR	-	-	-	-
https://cftr2.org/mutation/scientific/R117H/	-	-	-	-
https://www.pharmgkb.org/clinicalAnnotation/1447964187	-	-	-	-
https://www.pharmgkb.org/variant/PA166157519	-	-	-	-
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Text-mined citations for rs78655421 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.350G>A (p.Arg117His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs78655421 ...