ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3731G>A (p.Gly1244Glu)

gnomAD frequency: 0.00001  dbSNP: rs267606723
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000056386 SCV000071499 pathogenic Cystic fibrosis 2017-03-17 reviewed by expert panel research
PharmGKB RCV000211150 SCV000268279 drug response ivacaftor response - Efficacy 2021-03-24 reviewed by expert panel curation 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000056386 SCV000696985 pathogenic Cystic fibrosis 2016-03-31 criteria provided, single submitter clinical testing Variant summary: The CFTR c.3731G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Glu. 5/5 in-silico tools predict a damaging outcome for this variant, and G1244E has been shown to drastically reduce chloride channel activity and HCO3- transport by in vitro studies (Anderson et al 1992, Choi et al 2001, Yu et al 2012, and Sosnay et al 2013). This variant was found in 2/121206 control chromosomes at a frequency of 0.0000165, which does not exceed maximal expected frequency of a pathogenic CFTR allele (0.0129603). In addition, the CFTR2 database and several independent publications consider the variant pathogenic/CF-causing. Taken together, this variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000763160 SCV000893747 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004504 SCV001163549 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV000056386 SCV001169361 pathogenic Cystic fibrosis 2018-01-29 criteria provided, single submitter curation
Invitae RCV000056386 SCV001579154 pathogenic Cystic fibrosis 2023-10-25 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1244 of the CFTR protein (p.Gly1244Glu). This variant is present in population databases (rs267606723, gnomAD 0.002%). This missense change has been observed in individuals with cystic fibrosis and congenital absence of the vas deferens (PMID: 10636451, 10923036, 21520337, 22020151, 23974870). ClinVar contains an entry for this variant (Variation ID: 53797). 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: 11242048, 23974870). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV002247437 SCV002518687 pathogenic Hereditary pancreatitis 2022-05-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000056386 SCV002622033 pathogenic Cystic fibrosis 2021-04-30 criteria provided, single submitter clinical testing The p.G1244E pathogenic mutation (also known as c.3731G>A), located in coding exon 23 of the CFTR gene, results from a G to A substitution at nucleotide position 3731. The glycine at codon 1244 is replaced by glutamic acid, an amino acid with similar properties. This mutation was first described in a clinically affected individual with elevated sweat chloride levels and pancreatic insufficiency in conjunction with p.F508del (Devoto M et al. Am. J. Hum. Genet., 1991 Jun;48:1127-32). In another study, this mutation was identified in an individual with elevated sweat chloride levels, pancreatic insufficiency, and gastrointestinal and pulmonary symptoms of classic cystic fibrosis in conjunction with a frameshift alteration on the other chromosome (Kilinç MO et al. J. Med. Genet., 2000 Apr;37:307-9). This mutation was detected as homozygous in an individual with elevated sweat chloride levels and an overall clinical presentation consistent with cystic fibrosis (Petrova NV et al. Clin Genet, 2019 03;95:444-447). This mutation is typically associated with elevated sweat chloride levels, pancreatic insufficiency, and pulmonary symptoms (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). Functional analyses demonstrate that this mutation significantly reduces protein activity (Anderson MP et al. Science, 1992 Sep;257:1701-4; Choi JY et al. Nature, 2001 Mar;410:94-7; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics RCV003474587 SCV004213294 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2023-10-17 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV001831779 SCV004797234 pathogenic CFTR-related disorder 2024-02-16 criteria provided, single submitter clinical testing The CFTR c.3731G>A variant is predicted to result in the amino acid substitution p.Gly1244Glu. This variant has been reported in the homozygous or compound heterozygous state in individuals with cystic fibrosis (see, for example, Devoto et al. 1991. PubMed ID: 1709778; D'Apice et al. 2004. PubMed ID: 15614862; Mesbahi et al. 2016. PubMed ID: 27659740). It has also been detected in individuals with congenital bilateral absence of vas deferens (Supporting Table S5, Steiner et al. 2011. PubMed ID: 21520337). In vitro functional studies suggest this variant impacts protein function (Choi et al. 2001. PubMed ID: 11242048; Sosnay et al. 2013. PubMed ID: 23974870). In addition, alternative nucleotide changes affecting the same amino acid (p.Gly1244Arg, p.Gly1244Val) have also been reported in individuals with cystic fibrosis (Lucarelli et al. 2015. PubMed ID: 25910067; Ziętkiewicz et al. 2014. PubMed ID: 24586523; Savov et al. 1994. PubMed ID: 7516777). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Counsyl RCV000056386 SCV001132353 pathogenic Cystic fibrosis 2015-03-16 no assertion criteria provided clinical testing
Natera, Inc. RCV001831779 SCV002075875 pathogenic CFTR-related disorder 2017-03-17 no assertion criteria provided clinical testing

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