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

gnomAD frequency: 0.00001  dbSNP: rs267606723

Total submissions: 13

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
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-03-23	criteria provided, single submitter	clinical testing
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
PreventionGenetics, part of Exact Sciences	RCV001831779	SCV004797234	pathogenic	CFTR-related disorder	2024-02-16	no assertion criteria provided	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.