ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3181G>C (p.Gly1061Arg) (rs142394380)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000046807 SCV000245909 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078994 SCV000110863 likely pathogenic not provided 2018-03-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999884 SCV000883581 pathogenic not specified 2019-02-02 criteria provided, single submitter clinical testing The CFTR c.3181G>C, p.Gly1061Arg variant has been reported in cystic fibrosis patients (Alper 2004, Mercier 1993, Visich 2002, SickKids CFTR database, CFTR2 database), with variable presentation of pancreatic insufficiency (CFTR2 database). Functional characterization of the variant protein indicates that chloride conductance is severely impaired (CFTR2 database). The variant is listed in the ClinVar database (Variation ID: 53672), in the dbSNP variant database (rs142394380), and observed in the general population databases at a frequency of 0.02 percent in the 1000 Genomes Project, and 0.0077 percent in the Exome Variant Server. The glycine at residue 1061 is highly conserved, and computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as moderately pathogenic. References: CFTR2 database: https://cftr2.org/ Link to p.Gly1061Arg in SickKids database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=443 Alper OM et al. Identification of novel and rare mutations in California Hispanic and African American cystic fibrosis patients. Hum Mutat. 2004 Oct;24(4):353. 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. Visich A et al. Complete screening of the CFTR gene in Argentine cystic fibrosis patients. Clin Genet. 2002 Mar;61(3):207-13.
Baylor Genetics RCV001004296 SCV001163172 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000046807 SCV001169270 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000046807 SCV001361659 pathogenic Cystic fibrosis 2019-11-22 criteria provided, single submitter clinical testing Variant summary: CFTR c.3181G>C (p.Gly1061Arg) 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 4e-06 in 250828 control chromosomes (gnomAD). c.3181G>C has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Alper_2004, Bienvenu_1995, Chertkoff_1997, Mercier_1993). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to cause misprocessing and failure of maturation of CFTR resulting in its retention in the endoplasmic reticulum (Seibert_1996). Three ClinVar submitters including an expert panel (CFTR2) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000046807 SCV001548529 pathogenic Cystic fibrosis 2021-02-15 criteria provided, single submitter clinical testing
Invitae RCV000046807 SCV001590383 pathogenic Cystic fibrosis 2017-07-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1061 of the CFTR protein (p.Gly1061Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with cystic fibrosis, including many individuals who carry a second known CF-causing variant (PMID: 7683628, The Clinical and Functional TRanslation of CFTR (CFTR2) at http://cftr2.org). A different nucleotide change (c.3181G>A) resulting in the same protein effect (p.Gly1061Arg) has also been reported in individuals affected with cystic fibrosis (PMID: 8723695, 9084934). ClinVar contains an entry for this variant (Variation ID: 53672). An experimental study has shown that this missense change disrupts CFTR maturation and results in a loss of ion channel activity in cell culture (PMID: 8662892). For these reasons, this variant has been classified as Pathogenic.

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