NM_000492.4(CFTR):c.349C>G (p.Arg117Gly) AND Cystic fibrosis

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jan 25, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000670642.22

Allele description [Variation Report for NM_000492.4(CFTR):c.349C>G (p.Arg117Gly)]

NM_000492.4(CFTR):c.349C>G (p.Arg117Gly)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.349C>G (p.Arg117Gly)

HGVS:

NC_000007.14:g.117530974C>G
NG_016465.4:g.70191C>G
NM_000492.4:c.349C>GMANE SELECT
NP_000483.3:p.Arg117Gly
NP_000483.3:p.Arg117Gly
LRG_663t1:c.349C>G
LRG_663:g.70191C>G
LRG_663p1:p.Arg117Gly
NC_000007.13:g.117171028C>G
NM_000492.3:c.349C>G

Protein change:

R117G

Links:

dbSNP: rs77834169

NCBI 1000 Genomes Browser:

rs77834169

Molecular consequence:

NM_000492.4:c.349C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001167227	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 17, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001363740	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 21, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20706124, 23951356, 29805046, 29944384, 30888834, 11119745, 33922413 Citation Link,
SCV001821993	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002308825	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 11119745, 29944384, 30888834, 29805046, 7525450, 7529962, 11788090, 15482777, 21520337, 21783433, 22658665, 23974870, 24586523, 28492532
SCV002614882	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 4, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10923036, 11119745, 18687795, 22504961, 23951356, 23974870, 26277102, 28340353, 29805046 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation.

Lucarelli M, Narzi L, Pierandrei S, Bruno SM, Stamato A, d'Avanzo M, Strom R, Quattrucci S.

Genet Med. 2010 Sep;12(9):548-55. doi: 10.1097/GIM.0b013e3181ead634.

PubMed [citation]

PMID:: 20706124

Treatment of Pulmonary Disease of Cystic Fibrosis: A Comprehensive Review.

Girón Moreno RM, García-Clemente M, Diab-Cáceres L, Martínez-Vergara A, Martínez-García MÁ, Gómez-Punter RM.

Antibiotics (Basel). 2021 Apr 23;10(5). doi:pii: 486. 10.3390/antibiotics10050486. Review.

PubMed [citation]

PMID:: 33922413
PMCID:: PMC8144952

See all PubMed Citations (23)

Details of each submission

From Counsyl, SCV000795520.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Johns Hopkins Genomics, Johns Hopkins University, SCV001167227.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Previously reported disease-causing CFTR variant associated with varying clinical consequences. See www.CFTR2.org for phenotype information.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363740.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: CFTR c.349C>G (p.Arg117Gly) 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 2e-05 in 250944 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.349C>G has been reported in the literature in multiple compound heterozygous individuals affected with Cystic Fibrosis (Desai_2018, McCague_2019) as well as in individuals with pancreatitis (e.g., Masson_2013) and congenital bilateral absence of the vas deferens (e.g., Daudin_2000). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant results in approximately 35% overall function (compared to WT) (Raraigh_2018). Eight ClinVar submitters (evaluation after 2014) have cited the variant, with six submitters classifying the variant as pathogenic (n=3)/likely pathogenic (n=3), and two submitters classifying the variant as uncertain significance. Additionally, different missense variants affecting the same codon have been reported as pathogenic by our lab (p.R117C, p.R117H, p.R117L).Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001821993.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002308825.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 117 of the CFTR protein (p.Arg117Gly). This variant is present in population databases (rs77834169, gnomAD 0.004%). This missense change has been observed in individuals with clinical symptoms of CFTR-related conditions (PMID: 11119745, 29805046, 29944384, 30888834). ClinVar contains an entry for this variant (Variation ID: 53762). 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 have shown that this missense change affects CFTR function (PMID: 29805046). This variant disrupts the p.Arg117 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7525450, 7529962, 11788090, 15482777, 21520337, 21783433, 22658665, 23974870, 24586523). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002614882.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.R117G pathogenic mutation (also known as c.349C>G), located in coding exon 4 of the CFTR gene, results from a C to G substitution at nucleotide position 349. The arginine at codon 117 is replaced by glycine, an amino acid with dissimilar properties. The mutation has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed November 14, 2018). It has been described in the heterozygous state in a male with congenital bilateral absence of the vas deferens (CBAVD); a second CFTR alteration was not observed (Claustres M et al. Hum. Mutat., 2000;16:143-56; Daudin M et al. Fertil. Steril., 2000 Dec;74:1164-74). In addition, this mutation was observed in conjunction with p.N34S in the SPINK1 gene in an individual with idiopathic pancreatitis (Masson E et al. PLoS ONE. 2013; 8(8):e73522). In an in vitro study, the R117G protein had 35% of normal CFTR function (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants at the same position and in the same region (Liu F et al. Cell, 2017 03;169:85-95.e8). Furthermore, there are also multiple pathogenic alterations at this same position, including p.R117H and p.R117C (Thauvin-Robinet C et al. J. Med. Genet., 2013 Apr;50:220-7; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on available evidence to date, this variant has not been reported as causative of classic CF; however, it may contribute to the development of a CFTR-related disorder and is thus classified as as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000795520	Counsyl	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Nov 8, 2017)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000795520

Counsyl

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Nov 8, 2017)

unknown

clinical testing

Citation Link

Last Updated: Oct 26, 2024

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