ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2909G>A (p.Gly970Asp) (rs386134230)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000046718 SCV000924213 pathogenic Cystic fibrosis 2018-08-31 reviewed by expert panel research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000046718 SCV000245589 pathogenic Cystic fibrosis 2020-01-21 criteria provided, single submitter clinical testing The p.Gly970Asp variant in CFTR has been reported in the compound heterozygous state in a least 13 individuals of predominantly Asian ancestry with CFTR-related disorders (10 with cystic fibrosis and 3 with congenital bilateral absence of the vas deferens (CBAVD); Wagner 1999, Wine 2001, Goubau 2009, Li 2012, Tian 2016, Xu 2017, Amato 2019). In at least 10 of these individuals, the second identified variant was pathogenic or likely pathogenic. This variant has also been identified in 0.016% (3/18394) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that this variant impacts protein function (Wagner 1999, Amato 2019) and computational prediction tools and conservation analyses are consistent with pathogenicity. This variant is located in the first base of the exon, which is part of the 3’ splice region. Additional computational tools do not predict altered splicing. Additionally, this variant was classified as pathogenic on August 31st, 2018 by the ClinGen-approved CFTR2 expert panel (Variation ID 35854). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM3_Very Strong, PM2, PP3, PS3_Supporting.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002487 SCV001160438 pathogenic not specified 2019-04-04 criteria provided, single submitter clinical testing The CFTR c.2909G>A; p.Gly970Asp variant (rs386134230) is reported in the literature in numerous individuals affected with cystic fibrosis (CF) (Goubau 2009, Tian 2016, Wagner 1999, Xu 2017, CFTR2 database). This variant has been observed in affected individuals in trans to other pathogenic variants, and it is primarily associated with pancreatic-sufficient CF (Goubau 2009, Tian 2016, Wagner 1999, CFTR2 database). Additionally, this variant has been observed in individuals with congenital bilateral absence of the vas deferens (CBAVD) that also carried mild pathogenic variants (Li 2012). This variant is reported as likely pathogenic by several laboratories in ClinVar (Variation ID: 35854) and it is found on only three chromosomes (3/250920 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 970 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with this, the p.Gly970Asp variant protein exhibits 1.7% of wildtype chloride channel activity in CFBE cells (CFTR2 database) and shows decreased efflux activity in HEK cells (Wagner 1999). Additionally, another amino acid substitution at this codon (p.Gly970Arg) has been reported in individuals with pancreatic-insufficient CF and is considered pathogenic (Sosnay 2012, CFTR2 database). Based on available information, the p.Gly970Asp variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009 Aug;64(8):683-91. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 Jul;11(4):316-23. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. Tian X et al. p.G970D is the most frequent CFTR mutation in Chinese patients with cystic fibrosis. Hum Genome Var. 2016 Jan 7;3:15063. Wagner JA et al. Two novel mutations in a cystic fibrosis patient of Chinese origin. Hum Genet. 1999 Jun;104(6):511-5. Xu J et al. Four case reports of Chinese cystic fibrosis patients and literature review. Pediatr Pulmonol. 2017 Aug;52(8):1020-1028.
Baylor Genetics RCV001004490 SCV001163535 likely pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000046718 SCV000052160 likely pathogenic Cystic fibrosis 2015-10-02 no assertion criteria provided clinical testing
Counsyl RCV000046718 SCV000485692 likely pathogenic Cystic fibrosis 2016-01-29 no assertion criteria provided clinical testing

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