VCV000035865.81 - ClinVar

NM_000492.4(CFTR):c.3154T>G (p.Phe1052Val)

Germline

Top reviewed classifications are shown here.

Submission summary:

29 submissions

27 submitters

7 conditions

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

Identifiers

NM_000492.4(CFTR):c.3154T>G (p.Phe1052Val)

Variation ID: 35865 Accession: VCV000035865.81

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117611595 (GRCh38) [ NCBI UCSC ] 7: 117251649 (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	Oct 11, 2015	Oct 20, 2024	Mar 24, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.3154T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Phe1052Val	missense
NC_000007.14:g.117611595T>G
NC_000007.13:g.117251649T>G
NG_016465.4:g.150812T>G
NG_056128.2:g.4649T>G
LRG_663:g.150812T>G
LRG_663t1:c.3154T>G	LRG_663p1:p.Phe1052Val
	P13569:p.Phe1052Val

... more HGVS ... less HGVS

Protein change

F1052V

Other names

Canonical SPDI

NC_000007.14:117611594:T:G

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.

The Genome Aggregation Database (gnomAD) 0.00039

Exome Aggregation Consortium (ExAC) 0.00066

Trans-Omics for Precision Medicine (TOPMed) 0.00079

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00100

Links

dbSNP: rs150212784 ClinGen: CA327067 UniProtKB: P13569#VAR_000232 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
LOC111674472	-	-	-	GRCh38	-	400

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	Conflicting interpretations of pathogenicity (11)	criteria provided, conflicting classifications	Aug 13, 2024	RCV000046799.45
not provided	Conflicting interpretations of pathogenicity (9)	criteria provided, conflicting classifications	Jul 1, 2024	RCV000224816.55
ivacaftor response - Efficacy	drug response (1)	reviewed by expert panel	Mar 24, 2021	RCV000660777.11
Hereditary pancreatitis	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Feb 15, 2022	RCV000770985.12
CFTR-related disorder	Pathogenic (3)	criteria provided, single submitter	Mar 26, 2018	RCV001009471.12
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	-	RCV001004295.8
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (1)	criteria provided, single submitter	Mar 29, 2024	RCV003473140.2

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.
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: SCV000783016.2 First in ClinVar: Jul 09, 2018 Last updated: Dec 12, 2021 Comment: Drug is not necessarily used to treat response condition	Publications: PubMed (1) PubMed: 23891399 Other databases https://www.pharmgkb.org/variant… https://www.pharmgkb.org/variant/PA166164951 https://www.pharmgkb.org/clinica… https://www.pharmgkb.org/clinicalAnnotation/1449191708 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 (Mar 06, 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: SCV000280878.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016
Uncertain significance (Apr 27, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Affected status: yes Allele origin: maternal	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000897972.1 First in ClinVar: May 19, 2019 Last updated: May 19, 2019	Comment: This recessive variant was identified in a patient with repetitive pancreatitis. The patient harbours also a second variant (see above) in this gene in compound … (more) This recessive variant was identified in a patient with repetitive pancreatitis. The patient harbours also a second variant (see above) in this gene in compound heterozygosity (less) Age: 0-9 years Sex: female
Likely pathogenic (Mar 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV000992329.1 First in ClinVar: Sep 11, 2019 Last updated: Sep 11, 2019
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: SCV001163171.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020
Pathogenic (Mar 26, 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: SCV001169566.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918 Observation 1: Sex: male Observation 2: Sex: female
Likely pathogenic (May 03, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV001251678.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Uncertain significance (Mar 30, 2021)	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: SCV002507386.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022
Likely pathogenic (Apr 29, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary pancreatitis Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529711.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The CFTR c.3154T>G (p.F1052V) variant has been reported as homozygous and compound heterozygous with p.F508del in multiple individuals with cystic fibrosis (PMID: 18373402, 22892530, 30540547). … (more) The CFTR c.3154T>G (p.F1052V) variant has been reported as homozygous and compound heterozygous with p.F508del in multiple individuals with cystic fibrosis (PMID: 18373402, 22892530, 30540547). There are reports of homozygous and compound heterozygous individuals who are asymptomatic or have a non-classic cystic fibrosis phenotype, some with normal sweat tests (PMID: 29589582, 29168366, 33393655, 24204751, 19885835). This variant has been reported in individuals with pancreatitis (PMID: 20460946,17489851, 25704068, 25033378), but was also found in healthy controls (PMID: 17489851, 25033378), and was identified in two patients with pancreatic cancer (PMID: 19885835, 32113160). Functional studies have shown that this variant significantly decreases the open probability of the CFTR channel, resulting in a reduction of channel activity (PMID: 8662892, 8702904), but still retains a chloride transport of approximately 87% of the wildtype channel (PMID: 23974870, 23891399). This variant was observed in 21/10348 chromosomes in the Ashkenazi Jewish population, with 1 homozygote among all ethnicities, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 35865). Based on the current evidence available, this variant is interpreted as likely pathogenic. (less)	Publications: PubMed (17) PubMed: 18373402‚ 22892530‚ 30540547‚ 29589582‚ 29168366‚ 33393655‚ 24204751‚ 19885835‚ 20460946‚ 17489851‚ 25704068‚ 25033378‚ 32113160‚ 8662892‚ 8702904‚ 23974870‚ 23891399
Pathogenic (Feb 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580737.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PM3_STR, PS3_MOD, PS4_MOD, PM2_SUP, PP3	Number of individuals with the variant: 2 Sex: female
Uncertain significance (Nov 05, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: unknown	Mendelics Accession: SCV000886354.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Likely pathogenic (May 03, 2023)	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: SCV000601088.5 First in ClinVar: Jun 08, 2016 Last updated: Jan 06, 2024	Publications: PubMed (13) PubMed: 35418593‚ 7544319‚ 8662892‚ 18373402‚ 23891399‚ 8702904‚ 29168366‚ 15480987‚ 12439892‚ 12200467‚ 10970190‚ 36458240‚ 9521595 Comment: In the published literature, the variant has been reported as homozygous (PMIDs: 12439892 (2002) and 18373402 (2008)) or compound heterozygous in individuals with cystic fibrosis … (more) In the published literature, the variant has been reported as homozygous (PMIDs: 12439892 (2002) and 18373402 (2008)) or compound heterozygous in individuals with cystic fibrosis (PMIDs: 9521595 (1998), 12200467 (2002), 15480987 (2004), 29168366 (2017), and 36458240 (2022)) as well as in CFTR-related disorders (PMIDs: 7544319 (1995), 10970190 (2000), 19885835 (2010), 24204751 (2013), and 32150665 (2020)). In addition, functional studies indicate this variant has neutral effect on CFTR protein processing and chloride channel conductance but reduced certain gating and kinetic properties of the chloride channels (PMIDs: 8702904 (1996), 8662892 (1996), and 23891399 (2014)). The frequency of this variant in the general population, 0.006 (16/2664 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic. (less)
Pathogenic (Mar 21, 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: SCV000883565.3 First in ClinVar: Feb 17, 2019 Last updated: Feb 20, 2024	Comment: The CFTR c.3154T>G; p.Phe1052Val variant (rs150212784) has been reported in patients diagnosed with cystic fibrosis (Brancolini 1995, Lakeman 2008, Mercier 1993, Onay 1998, Sosnay 2013) … (more) The CFTR c.3154T>G; p.Phe1052Val variant (rs150212784) has been reported in patients diagnosed with cystic fibrosis (Brancolini 1995, Lakeman 2008, Mercier 1993, Onay 1998, Sosnay 2013) and CFTR-related disorders (Gallati 2009, Pelletier 2010, Puechal 2011, Tzetis 2007), and associated with varying clinical consequences (CFTR2 database). Functional studies indicate that the variant protein has normal maturation and conductance (Sosnay 2013, Van Goor 2014), but altered channel kinetics (Cotten 1996, Seibert 1996). The variant is reported in ClinVar (Variation ID: 35865). It is found in the general population with an overall allele frequency of 0.06% (177/281760 alleles, including 1 homozygote) in the Genome Aggregation Database. The phenylalanine at codon 1052 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.948). Based on available information, this variant is considered to be pathogenic with a variable presentation of clinical phenotypes. References: CFTR2 database: http://cftr2.org/ Brancolini V et al. Search for mutations in pancreatic sufficient cystic fibrosis Italian patients: detection of 90% of molecular defects and identification of three novel mutations. Hum Genet. 1995; 96(3):312-8. Cotten J et al. Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator. J Biol Chem. 1996; 271(35):21279-84. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009; 19(5):685-94. Lakeman P et al. CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening. Genet Test. 2008;12(1):25-35. Mercier B et al. Identification of eight novel mutations in a collaborative analysis of a part of the second transmembrane domain of the CFTR gene. Genomics. 1993; 16(1):296-7. Onay T et al. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998; 102(2):224-30. Pelletier A et al. CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. Pancreatology. 2010; 10(2-3):158-64. Puechal X et al. Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. Ann Rheum Dis. 2011; 70(4):653-9. Seibert F et al. Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity. J Biol Chem. 1996; 271(25):15139-45. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. Tzetis M et al. Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis. Clin Genet. 2007; 71(5):451-7. 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; 13(1):29-36. (less)
Likely pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004807193.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Likely pathogenic (Feb 29, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001180126.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (14) PubMed: 11883825‚ 18373402‚ 23891399‚ 23974870‚ 27214204‚ 27469177‚ 28603918‚ 32150665‚ 34949556‚ 7683628‚ 8662892‚ 8702904‚ 9521595‚ 9620832 Comment: The p.F1052V variant (also known as c.3154T>G), located in coding exon 20 of the CFTR gene, results from a T to G substitution at nucleotide … (more) The p.F1052V variant (also known as c.3154T>G), located in coding exon 20 of the CFTR gene, results from a T to G substitution at nucleotide position 3154. The phenylalanine at codon 1052 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 02/28/2024). This variant has also been identified in the homozygous state and in trans/likely in trans with another CFTR variant in individuals with a wide range of clinical manifestations, including asymptomatic patients as well as those with cystic fibrosis or CFTR-related disorder (Kanavakis E et al. Mol Hum Reprod, 1998 Apr;4:333-7; Onay T et al. Hum Genet, 1998 Feb;102:224-30; Padoan R et al. Acta Paediatr, 2002;91:82-7; Lakeman P et al. Genet. Test., 2008 Mar;12:25-35; Claustres M et al. Hum Mutat, 2017 Oct;38:1297-1315; Terlizzi V et al. Pediatr Pulmonol, 2020 May;55:1089-1093; Hatton A et al. J Cyst Fibros, 2022 May;21:448-455). In vitro studies demonstrated that this variant does not impact maturation of CFTR protein, but reduces CFTR function (Cotten JF et al. J. Biol. Chem., 1996 Aug;271:21279-84; Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45; Sosnay PR et al. Nat Genet, 2013 Oct;45:1160-7; Van Goor F et al. J Cyst Fibros, 2014 Jan;13:29-36). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis; however, it likely contributes to the development of a CFTR-related disorder. This alteration is thus classified as likely pathogenic. (less)
Likely pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Cystic fibrosis Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005052072.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Mar 29, 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: SCV004211621.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (Mar 04, 2024)	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: SCV000052171.10 First in ClinVar: Apr 04, 2013 Last updated: Jun 29, 2024	Publications: PubMed (37) PubMed: 11354633‚ 7529962‚ 15463907‚ 9239681‚ 10801389‚ 19885835‚ 17489851‚ 1284534‚ 8662892‚ 8702904‚ 7536669‚ 18373402‚ 9521595‚ 11883825‚ 12439892‚ 7544319‚ 20460946‚ 20021716‚ 7683628‚ 21131649‚ 10970190‚ 19318035‚ 12200467‚ 15480987‚ 9620832‚ 23974870‚ 22892530‚ 23891399‚ 28603918‚ 28408918‚ 26436105‚ 25033378‚ 29589582‚ 29168366‚ 23523379‚ 30540547‚ 32150665 Comment: Variant summary: CFTR c.3154T>G (p.Phe1052Val) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded … (more) Variant summary: CFTR c.3154T>G (p.Phe1052Val) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 250362 control chromosomes in the gnomAD database, including one homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.00065 vs 0.013), allowing no conclusion about variant significance. c.3154T>G has been reported in the literature in individuals affected with Cystic Fibrosis, both in homozygous patients (e.g. Lakeman_2008) and in compound heterozygosity with other known pathogenic mutations (e.g. Brancolini_1995, Onay_1998, Sobczynska-Tomaszewska_2013, Levy_2019). These data indicate that the variant is likely to be associated with disease, however no cosegregation studies are reported in the literature. In addition,the variant has frequently been associated with non-classical manifestations of disease such as pancreatic sufficiency (e.g. Brancolini_1995) and borderline or normal sweat chloride levels (e.g. Hirtz_2004, Basaran_2017), and was found in compound heterozygosity with a known pathogenic mutation in several patients who were asymptomatic at the time of testing (e.g. Boyne_2000, Grangeia_2018). These data strongly suggest that this variant is a "mild" mutation with varying clinical consequences. The variant has also been detected in individuals with other CFTR-related disorders such as CBAVD (Congenital Bilateral Absence of Vas Deferens; e.g. Mercier_1995) and pancreatitis (e.g. Tzetis_2007, Pelletier_2010). In addition the variant has been found in several patients with other lung diseases such as rheumatoid-associated bronchiectasis (e.g. Puechal_2011) and COPD (e.g. Divac_2004) without strong evidence for causality. Several publications report experimental evidence evaluating an impact on protein function. In vitro experiments indicated that the variant mildly affects chloride channel function (Sosnay_2013, Van Goor_2014). In addition, this variant was found to alter the regulation and gating properties of chloride channels, though cAMP-stimulated efflux of chlorine channel was normal (Seibert_1996, Cotton_1996). The following publications have been ascertained in the context of this evaluation (PMID: 29168366, 10970190, 7544319, 28603918, 8702904, 9239681, 15463907, 28408918, 20021716, 7536669, 10801389, 29589582, 15480987, 9620832, 12439892, 25033378, 18373402, 30540547, 19885835, 7529962, 7683628, 9521595, 11883825, 20460946, 21131649, 23523379, 19318035, 8662892, 22892530, 23974870, 32150665, 26436105, 1284534, 17489851, 11354633, 23891399, 12200467). ClinVar contains an entry for this variant (Variation ID: 35865). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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: SCV005197465.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Uncertain significance (Jun 30, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001872928.4 First in ClinVar: Sep 19, 2021 Last updated: Sep 16, 2024	Comment: Published functional studies suggest regulation and gating of the channel is affected, however, chloride conductance capabilities are similar to wildtype (PMID: 8702904, 8662892, 23974870); Observed … (more) Published functional studies suggest regulation and gating of the channel is affected, however, chloride conductance capabilities are similar to wildtype (PMID: 8702904, 8662892, 23974870); Observed in apparent homozygous state or with a pathogenic CFTR variant in individuals with cystic fibrosis (CF) and CFTR-related disorders but also in individuals with no reported features of CF (PMID: 7544319, 12439892, 18373402, 24204751, 29168366, 29589582, 33393655, 34860163, 27214204); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 25033378, 25087612, 26437683, 36207272, 36409994, 35997436, 31759907, 21131649, 23974870, 20460946, 20021716, 23891399, 24204751, 26823392, 25704068, 29292091, 29805046, 9239681, 18373402, 17489851, 19885835, 12843327, 11883825, 10801389, 15463907, 7683628, 29589582, 29168366, 19318035, 12439892, 9521595, 27214204, 31331863, 32003480, 31005549, 30561903, 32357917, 30146269, 32113160, 32773111, 32819855, 33393655, 32926152, 33470563, 32484936, 34426522, 34756682, 34949556, 8662892, 8702904, 28408918, 34413153, 34996830, 34797250, 30540547, Turkyilmaz[CaseReport]2021, Oraimi[CaseReport]2022, 34860163, 22892530, 7544319, 37046605, 30938940, 36458240, 35418593, 36650664, 32003094, 37823318, 34405919, 38493004, 37628659, 38203285, 38392563, 38744964, 38515211) (less)
Likely pathogenic (Aug 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: biparental	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals Accession: SCV005367964.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024
Pathogenic (Jul 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: SCV001501421.23 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Comment: CFTR: PM1:Strong, PM3:Strong, PS3:Moderate, PM2:Supporting, PP3 Number of individuals with the variant: 15
Uncertain significance (Jul 06, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000700272.2 First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018	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: 7 Sex: mixed
Uncertain significance (Dec 17, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714244.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Number of individuals with the variant: 1
Likely pathogenic (Jul 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: germline	Genome-Nilou Lab Accession: SCV001781360.1 First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021	Sex: mixed
Uncertain significance (Feb 01, 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: SCV000074812.11 First in ClinVar: Jul 03, 2013 Last updated: Feb 28, 2024	Publications: PubMed (15) PubMed: 28492532‚ 9239681‚ 20460946‚ 18373402‚ 12439892‚ 17489851‚ 19885835‚ 12843327‚ 24204751‚ 11883825‚ 10801389‚ 19318035‚ 23891399‚ 26823392‚ 23974870 Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1052 of the CFTR protein (p.Phe1052Val). … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1052 of the CFTR protein (p.Phe1052Val). This variant is present in population databases (rs150212784, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been reported in individuals affected with cystic fibrosis, congenital absence of the vas deferens, pancreatitis, pancreatic cancer, and bronchiectasis (PMID: 9239681, 20460946, 18373402, 12439892, 17489851, 19885835, 12843327). However, this variant has also been reported to co-occur with p.Phe508del in at least one asymptomatic individual with borderline sweat chloride levels (PMID: 24204751) and with mild pathogenic variants in individuals with normal sweat chloride tests (PMID: 19885835, 11883825, 10801389, 19318035). ClinVar contains an entry for this variant (Variation ID: 35865). 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%. Experimental studies in cultured cells have shown that CFTR protein with this missense variant retains ~87% of chloride transport activity relative to wild-type protein (PMID: 23891399, 26823392, 23974870). By comparison, most severe pathogenic variants, such as p.Phe508del, exhibit ~0-1% transport activity in these same assays. The clinical impact of this small effect on protein function is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (-)	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: SCV001553295.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The CFTR p.Phe1052Val variant was identified in 7 of 2126 proband chromosomes (frequency: 0.003) from individuals or families with cystic fibrosis (CF) or pancreatitis and … (more) The CFTR p.Phe1052Val variant was identified in 7 of 2126 proband chromosomes (frequency: 0.003) from individuals or families with cystic fibrosis (CF) or pancreatitis and was identified in 4 of 422 control chromosomes (frequency: 0.009) (Tzets_2007_PMID: 17489851; Grangeia_2018_PMID: 29589582; Pelletier_2010_PMID: 20460946). The variant was also identified in dbSNP (ID: rs150212784), ClinVar (classified as a VUS by five submitters, likely pathogenic by two submitters and as pathogenic by two submitters) and LOVD 3.0; the variant was not identified in Cosmic. The variant was also identified in control databases in 177 of 281760 chromosomes (1 homozygous) at a frequency of 0.000628 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 21 of 10348 chromosomes (freq: 0.002029), Other in 9 of 7174 chromosomes (freq: 0.001255), European (non-Finnish) in 117 of 128594 chromosomes (freq: 0.00091), Latino in 22 of 35218 chromosomes (freq: 0.000625), European (Finnish) in 6 of 25038 chromosomes (freq: 0.00024) and South Asian in 2 of 30532 chromosomes (freq: 0.000066), while the variant was not observed in the African and East Asian populations. The F1052V variant was identified in a Portuguese child who also carried the classic deltaF508 variant, however this child was not affected with CF (Grangeia_2018_PMID: 29589582). The F1052V and deltaF508 variants have also been reported in the compound heterozygous state in a patient with pancreatic cancer, however this individual was not affected with CF; this suggest that the F1052V variant may not be causal of CF (McWilliams_2010_PMID: 19885835). The p.Phe1052 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
Likely pathogenic (Mar 30, 2021)	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: SCV002507472.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022
Uncertain significance (Sep 27, 2024)	no assertion criteria provided Method: clinical testing	CFTR-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005356800.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The CFTR c.3154T>G variant is predicted to result in the amino acid substitution p.Phe1052Val. This variant has been reported in 33 patients with cystic fibrosis … (more) The CFTR c.3154T>G variant is predicted to result in the amino acid substitution p.Phe1052Val. This variant has been reported in 33 patients with cystic fibrosis and an average sweat chloride level of 47mEq/L (www.cftr2.org). Functional studies indicated that the p.Phe1052Val variant did not alter CFTR chloride channel conductance or expression in cell lines (see supplement table 2 in Sosnay et al. 2013. PubMed ID: 23974870; Van Goor et al. 2014. PubMed ID: 23891399). This variant has been reported in individuals affected with suspected cystic fibrosis (see for example: Basaran et al. 2017. PubMed ID: 29168366; Kilinc et al. 2002. PubMed ID: 12439892; Lakeman et al. 2008. PubMed ID: 18373402; Vrettou et al. 2002. PubMed ID: 12200467), but has also been published as a heterozygous variant in the absence of a second possible causative variant, and/or in patients with limited clinical or genetic evidence to support pathogenicity (see for example: Divac et al. 2004. PubMed ID: 15463907; Tzetis et al. 2001. PubMed ID: 11354633; Kilinc et al. 2002. PubMed ID: 12439892; McWilliams et al. 2010. PubMed ID: 19885835; Grangeia et al. 2018. PubMed ID: 29589582). This variant is reported in 0.20% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including 1 homozygote. In ClinVar, this variant has been interpreted as uncertain, likely pathogenic, or pathogenic by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/35865/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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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:

In the published literature, the variant has been reported as homozygous (PMIDs: 12439892 (2002) and 18373402 (2008)) or compound heterozygous in individuals with cystic fibrosis (PMIDs: 9521595 (1998), 12200467 (2002), 15480987 (2004), 29168366 (2017), and 36458240 (2022)) as well as in CFTR-related disorders (PMIDs: 7544319 (1995), 10970190 (2000), 19885835 (2010), 24204751 (2013), and 32150665 (2020)). In addition, functional studies indicate this variant has neutral effect on CFTR protein processing and chloride channel conductance but reduced certain gating and kinetic properties of the chloride channels (PMIDs: 8702904 (1996), 8662892 (1996), and 23891399 (2014)). The frequency of this variant in the general population, 0.006 (16/2664 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.

Comment:

The CFTR c.3154T>G; p.Phe1052Val variant (rs150212784) has been reported in patients diagnosed with cystic fibrosis (Brancolini 1995, Lakeman 2008, Mercier 1993, Onay 1998, Sosnay 2013) and CFTR-related disorders (Gallati 2009, Pelletier 2010, Puechal 2011, Tzetis 2007), and associated with varying clinical consequences (CFTR2 database). Functional studies indicate that the variant protein has normal maturation and conductance (Sosnay 2013, Van Goor 2014), but altered channel kinetics (Cotten 1996, Seibert 1996). The variant is reported in ClinVar (Variation ID: 35865). It is found in the general population with an overall allele frequency of 0.06% (177/281760 alleles, including 1 homozygote) in the Genome Aggregation Database. The phenylalanine at codon 1052 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.948). Based on available information, this variant is considered to be pathogenic with a variable presentation of clinical phenotypes. References: CFTR2 database: http://cftr2.org/ Brancolini V et al. Search for mutations in pancreatic sufficient cystic fibrosis Italian patients: detection of 90% of molecular defects and identification of three novel mutations. Hum Genet. 1995; 96(3):312-8. Cotten J et al. Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator. J Biol Chem. 1996; 271(35):21279-84. Gallati S et al Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009; 19(5):685-94. Lakeman P et al. CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening. Genet Test. 2008;12(1):25-35. Mercier B et al. Identification of eight novel mutations in a collaborative analysis of a part of the second transmembrane domain of the CFTR gene. Genomics. 1993; 16(1):296-7. Onay T et al. Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I). Hum Genet. 1998; 102(2):224-30. Pelletier A et al. CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. Pancreatology. 2010; 10(2-3):158-64. Puechal X et al. Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. Ann Rheum Dis. 2011; 70(4):653-9. Seibert F et al. Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity. J Biol Chem. 1996; 271(25):15139-45. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. Tzetis M et al. Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis. Clin Genet. 2007; 71(5):451-7. 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; 13(1):29-36.

Comment:

The p.F1052V variant (also known as c.3154T>G), located in coding exon 20 of the CFTR gene, results from a T to G substitution at nucleotide position 3154. The phenylalanine at codon 1052 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 02/28/2024). This variant has also been identified in the homozygous state and in trans/likely in trans with another CFTR variant in individuals with a wide range of clinical manifestations, including asymptomatic patients as well as those with cystic fibrosis or CFTR-related disorder (Kanavakis E et al. Mol Hum Reprod, 1998 Apr;4:333-7; Onay T et al. Hum Genet, 1998 Feb;102:224-30; Padoan R et al. Acta Paediatr, 2002;91:82-7; Lakeman P et al. Genet. Test., 2008 Mar;12:25-35; Claustres M et al. Hum Mutat, 2017 Oct;38:1297-1315; Terlizzi V et al. Pediatr Pulmonol, 2020 May;55:1089-1093; Hatton A et al. J Cyst Fibros, 2022 May;21:448-455). In vitro studies demonstrated that this variant does not impact maturation of CFTR protein, but reduces CFTR function (Cotten JF et al. J. Biol. Chem., 1996 Aug;271:21279-84; Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45; Sosnay PR et al. Nat Genet, 2013 Oct;45:1160-7; Van Goor F et al. J Cyst Fibros, 2014 Jan;13:29-36). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis; however, it likely contributes to the development of a CFTR-related disorder. This alteration is thus classified as likely pathogenic.

Comment:

Variant summary: CFTR c.3154T>G (p.Phe1052Val) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 250362 control chromosomes in the gnomAD database, including one homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.00065 vs 0.013), allowing no conclusion about variant significance. c.3154T>G has been reported in the literature in individuals affected with Cystic Fibrosis, both in homozygous patients (e.g. Lakeman_2008) and in compound heterozygosity with other known pathogenic mutations (e.g. Brancolini_1995, Onay_1998, Sobczynska-Tomaszewska_2013, Levy_2019). These data indicate that the variant is likely to be associated with disease, however no cosegregation studies are reported in the literature. In addition,the variant has frequently been associated with non-classical manifestations of disease such as pancreatic sufficiency (e.g. Brancolini_1995) and borderline or normal sweat chloride levels (e.g. Hirtz_2004, Basaran_2017), and was found in compound heterozygosity with a known pathogenic mutation in several patients who were asymptomatic at the time of testing (e.g. Boyne_2000, Grangeia_2018). These data strongly suggest that this variant is a "mild" mutation with varying clinical consequences. The variant has also been detected in individuals with other CFTR-related disorders such as CBAVD (Congenital Bilateral Absence of Vas Deferens; e.g. Mercier_1995) and pancreatitis (e.g. Tzetis_2007, Pelletier_2010). In addition the variant has been found in several patients with other lung diseases such as rheumatoid-associated bronchiectasis (e.g. Puechal_2011) and COPD (e.g. Divac_2004) without strong evidence for causality. Several publications report experimental evidence evaluating an impact on protein function. In vitro experiments indicated that the variant mildly affects chloride channel function (Sosnay_2013, Van Goor_2014). In addition, this variant was found to alter the regulation and gating properties of chloride channels, though cAMP-stimulated efflux of chlorine channel was normal (Seibert_1996, Cotton_1996). The following publications have been ascertained in the context of this evaluation (PMID: 29168366, 10970190, 7544319, 28603918, 8702904, 9239681, 15463907, 28408918, 20021716, 7536669, 10801389, 29589582, 15480987, 9620832, 12439892, 25033378, 18373402, 30540547, 19885835, 7529962, 7683628, 9521595, 11883825, 20460946, 21131649, 23523379, 19318035, 8662892, 22892530, 23974870, 32150665, 26436105, 1284534, 17489851, 11354633, 23891399, 12200467). ClinVar contains an entry for this variant (Variation ID: 35865). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

Published functional studies suggest regulation and gating of the channel is affected, however, chloride conductance capabilities are similar to wildtype (PMID: 8702904, 8662892, 23974870); Observed in apparent homozygous state or with a pathogenic CFTR variant in individuals with cystic fibrosis (CF) and CFTR-related disorders but also in individuals with no reported features of CF (PMID: 7544319, 12439892, 18373402, 24204751, 29168366, 29589582, 33393655, 34860163, 27214204); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 25033378, 25087612, 26437683, 36207272, 36409994, 35997436, 31759907, 21131649, 23974870, 20460946, 20021716, 23891399, 24204751, 26823392, 25704068, 29292091, 29805046, 9239681, 18373402, 17489851, 19885835, 12843327, 11883825, 10801389, 15463907, 7683628, 29589582, 29168366, 19318035, 12439892, 9521595, 27214204, 31331863, 32003480, 31005549, 30561903, 32357917, 30146269, 32113160, 32773111, 32819855, 33393655, 32926152, 33470563, 32484936, 34426522, 34756682, 34949556, 8662892, 8702904, 28408918, 34413153, 34996830, 34797250, 30540547, Turkyilmaz[CaseReport]2021, Oraimi[CaseReport]2022, 34860163, 22892530, 7544319, 37046605, 30938940, 36458240, 35418593, 36650664, 32003094, 37823318, 34405919, 38493004, 37628659, 38203285, 38392563, 38744964, 38515211)

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1052 of the CFTR protein (p.Phe1052Val). This variant is present in population databases (rs150212784, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been reported in individuals affected with cystic fibrosis, congenital absence of the vas deferens, pancreatitis, pancreatic cancer, and bronchiectasis (PMID: 9239681, 20460946, 18373402, 12439892, 17489851, 19885835, 12843327). However, this variant has also been reported to co-occur with p.Phe508del in at least one asymptomatic individual with borderline sweat chloride levels (PMID: 24204751) and with mild pathogenic variants in individuals with normal sweat chloride tests (PMID: 19885835, 11883825, 10801389, 19318035). ClinVar contains an entry for this variant (Variation ID: 35865). 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%. Experimental studies in cultured cells have shown that CFTR protein with this missense variant retains ~87% of chloride transport activity relative to wild-type protein (PMID: 23891399, 26823392, 23974870). By comparison, most severe pathogenic variants, such as p.Phe508del, exhibit ~0-1% transport activity in these same assays. The clinical impact of this small effect on protein function is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The CFTR p.Phe1052Val variant was identified in 7 of 2126 proband chromosomes (frequency: 0.003) from individuals or families with cystic fibrosis (CF) or pancreatitis and was identified in 4 of 422 control chromosomes (frequency: 0.009) (Tzets_2007_PMID: 17489851; Grangeia_2018_PMID: 29589582; Pelletier_2010_PMID: 20460946). The variant was also identified in dbSNP (ID: rs150212784), ClinVar (classified as a VUS by five submitters, likely pathogenic by two submitters and as pathogenic by two submitters) and LOVD 3.0; the variant was not identified in Cosmic. The variant was also identified in control databases in 177 of 281760 chromosomes (1 homozygous) at a frequency of 0.000628 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 21 of 10348 chromosomes (freq: 0.002029), Other in 9 of 7174 chromosomes (freq: 0.001255), European (non-Finnish) in 117 of 128594 chromosomes (freq: 0.00091), Latino in 22 of 35218 chromosomes (freq: 0.000625), European (Finnish) in 6 of 25038 chromosomes (freq: 0.00024) and South Asian in 2 of 30532 chromosomes (freq: 0.000066), while the variant was not observed in the African and East Asian populations. The F1052V variant was identified in a Portuguese child who also carried the classic deltaF508 variant, however this child was not affected with CF (Grangeia_2018_PMID: 29589582). The F1052V and deltaF508 variants have also been reported in the compound heterozygous state in a patient with pancreatic cancer, however this individual was not affected with CF; this suggest that the F1052V variant may not be causal of CF (McWilliams_2010_PMID: 19885835). The p.Phe1052 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

Comment:

The CFTR c.3154T>G variant is predicted to result in the amino acid substitution p.Phe1052Val. This variant has been reported in 33 patients with cystic fibrosis and an average sweat chloride level of 47mEq/L (www.cftr2.org). Functional studies indicated that the p.Phe1052Val variant did not alter CFTR chloride channel conductance or expression in cell lines (see supplement table 2 in Sosnay et al. 2013. PubMed ID: 23974870; Van Goor et al. 2014. PubMed ID: 23891399). This variant has been reported in individuals affected with suspected cystic fibrosis (see for example: Basaran et al. 2017. PubMed ID: 29168366; Kilinc et al. 2002. PubMed ID: 12439892; Lakeman et al. 2008. PubMed ID: 18373402; Vrettou et al. 2002. PubMed ID: 12200467), but has also been published as a heterozygous variant in the absence of a second possible causative variant, and/or in patients with limited clinical or genetic evidence to support pathogenicity (see for example: Divac et al. 2004. PubMed ID: 15463907; Tzetis et al. 2001. PubMed ID: 11354633; Kilinc et al. 2002. PubMed ID: 12439892; McWilliams et al. 2010. PubMed ID: 19885835; Grangeia et al. 2018. PubMed ID: 29589582). This variant is reported in 0.20% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including 1 homozygote. In ClinVar, this variant has been interpreted as uncertain, likely pathogenic, or pathogenic by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/35865/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Prevalence and Characteristics of Cystic Fibrosis in Omani Children: A Multi-center Cross-sectional Study.	Al Oraimi S	Oman medical journal	2022	PMID: 36458240
Spatial covariance analysis reveals the residue-by-residue thermodynamic contribution of variation to the CFTR fold.	Anglès F	Communications biology	2022	PMID: 35418593
Reclassifying inconclusive diagnosis after newborn screening for cystic fibrosis. Moving forward.	Hatton A	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2022	PMID: 34949556
Cystic fibrosis or not? Familial occurrence of a rare mutation in the CFTR gene.	Zapolnik P	Advances in respiratory medicine	2020	PMID: 33393655
Trend of sweat chloride values in a cohort of patients carrying CFTR mutations of varying clinical consequence: Is there a risk of increasing sweat chloride over time?	Terlizzi V	Pediatric pulmonology	2020	PMID: 32150665
A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants.	Earl J	EBioMedicine	2020	PMID: 32113160
Identification of molecular signatures of cystic fibrosis disease status with plasma-based functional genomics.	Levy H	Physiological genomics	2019	PMID: 30540547
Spectrum of CFTR gene sequence variants in a northern Portugal population.	Grangeia A	Pulmonology	2018	PMID: 29589582
Normal sweat chloride test does not rule out cystic fibrosis.	Başaran AE	The Turkish journal of pediatrics	2017	PMID: 29168366
CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants.	Claustres M	Human mutation	2017	PMID: 28603918
CFTR Gene Mutations in the Egyptian Population: Current and Future Insights for Genetic Screening Strategy.	El-Seedy AS	Frontiers in genetics	2017	PMID: 28408918
Molecular Genetics of Cystic Fibrosis Transmembrane Conductance Regulator: Genotype and Phenotype.	Sosnay PR	Pediatric clinics of North America	2016	PMID: 27469177
Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California.	Salinas DB	PloS one	2016	PMID: 27214204
From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations.	Veit G	Molecular biology of the cell	2016	PMID: 26823392
Validation of a semiconductor next-generation sequencing assay for the clinical genetic screening of CFTR.	Trujillano D	Molecular genetics & genomic medicine	2015	PMID: 26436105
Natural history of pancreatic involvement in paediatric inflammatory bowel disease.	Martinelli M	Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver	2015	PMID: 25704068
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
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
In vivo readout of CFTR function: ratiometric measurement of CFTR-dependent secretion by individual, identifiable human sweat glands.	Wine JJ	PloS one	2013	PMID: 24204751
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
PGD for cystic fibrosis patients and couples at risk of an additional genetic disorder combined with 24-chromosome aneuploidy testing.	Rechitsky S	Reproductive biomedicine online	2013	PMID: 23523379
Newborn screening for cystic fibrosis: Polish 4 years' experience with CFTR sequencing strategy.	Sobczyńska-Tomaszewska A	European journal of human genetics : EJHG	2013	PMID: 22892530
Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis.	Puéchal X	Annals of the rheumatic diseases	2011	PMID: 21131649
CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation.	Pelletier AL	Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]	2010	PMID: 20460946
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
Borderline sweat test: Utility and limits of genetic analysis for the diagnosis of cystic fibrosis.	Seia M	Clinical biochemistry	2009	PMID: 19318035
CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening.	Lakeman P	Genetic testing	2008	PMID: 18373402
Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis.	Tzetis M	Clinical genetics	2007	PMID: 17489851
CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis.	Hirtz S	Gastroenterology	2004	PMID: 15480987
High frequency of the R75Q CFTR variation in patients with chronic obstructive pulmonary disease.	Divac A	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2004	PMID: 15463907
High frequency of T9 and CFTR mutations in children with idiopathic bronchiectasis.	Ninis VN	Journal of medical genetics	2003	PMID: 12843327
Highest heterogeneity for cystic fibrosis: 36 mutations account for 75% of all CF chromosomes in Turkish patients.	Kilinç MO	American journal of medical genetics	2002	PMID: 12439892
Multiplex sequence variation detection throughout the CFTR gene appropriate for preimplantation genetic diagnosis in populations with heterogeneity of cystic fibrosis mutations.	Vrettou C	Molecular human reproduction	2002	PMID: 12200467
Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis.	Padoan R	Acta paediatrica (Oslo, Norway : 1992)	2002	PMID: 11883825
CFTR gene mutations--including three novel nucleotide substitutions--and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease.	Tzetis M	Human genetics	2001	PMID: 11354633
Many deltaF508 heterozygote neonates with transient hypertrypsinaemia have a second, mild CFTR mutation.	Boyne J	Journal of medical genetics	2000	PMID: 10970190
High frequency of cystic fibrosis transmembrane regulator mutation L997F in patients with recurrent idiopathic pancreatitis and in newborns with hypertrypsinemia.	Gomez Lira M	American journal of human genetics	2000	PMID: 10801389
Cystic fibrosis mutation screening in CBAVD patients and men with obstructive azoospermia or severe oligozoospermia.	Kanavakis E	Molecular human reproduction	1998	PMID: 9620832
Analysis of the CFTR gene in Turkish cystic fibrosis patients: identification of three novel mutations (3172delAC, P1013L and M1028I).	Onay T	Human genetics	1998	PMID: 9521595
Mutations in the cystic fibrosis gene in men with congenital bilateral absence of the vas deferens.	De Braekeleer M	Molecular human reproduction	1996	PMID: 9239681
Effect of cystic fibrosis-associated mutations in the fourth intracellular loop of cystic fibrosis transmembrane conductance regulator.	Cotten JF	The Journal of biological chemistry	1996	PMID: 8702904
Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity.	Seibert FS	The Journal of biological chemistry	1996	PMID: 8662892
Search for mutations in pancreatic sufficient cystic fibrosis Italian patients: detection of 90% of molecular defects and identification of three novel mutations.	Brancolini V	Human genetics	1995	PMID: 7544319
Is congenital bilateral absence of vas deferens a primary form of cystic fibrosis? Analyses of the CFTR gene in 67 patients.	Mercier B	American journal of human genetics	1995	PMID: 7529962
Detection of point mutations by capillary electrophoresis in liquid polymers in temporal thermal gradients.	Gelfi C	Electrophoresis	1994	PMID: 7536669
Identification of eight novel mutations in a collaborative analysis of a part of the second transmembrane domain of the CFTR gene.	Mercier B	Genomics	1993	PMID: 7683628
Mutations and sequence variations detected in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: a report from the Cystic Fibrosis Genetic Analysis Consortium.	Tsui LC	Human mutation	1992	PMID: 1284534
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR	-	-	-	-
https://www.pharmgkb.org/clinicalAnnotation/1449191708	-	-	-	-
https://www.pharmgkb.org/variant/PA166164951	-	-	-	-
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Text-mined citations for rs150212784 ...

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.3154T>G (p.Phe1052Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs150212784 ...