ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3095A>G (p.Tyr1032Cys)

gnomAD frequency: 0.00002  dbSNP: rs144055758
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029516 SCV000052167 pathogenic Cystic fibrosis 2020-08-28 criteria provided, single submitter clinical testing Variant summary: CFTR c.3095A>G (p.Tyr1032Cys) 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 1.6e-05 in 251624 control chromosomes. c.3095A>G has been reported in the literature and in multiple databases in compound heterozygous individuals with varying clinical consequences, ranging from Congenital Bilateral Absence of the Vas Deferens (CBAVD) to Cystic Fibrosis (usually with pancreatic sufficiency). There are 16 patients listed with this variant in the CFTR2 database, 27% of which are reported as pancreatic insufficient. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, indicating that the variant results in 10%-<30% of normal CFTR activity (e.g. Raraigh_2018, Han_2018, McCague_2019). Five other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000591587 SCV000603056 pathogenic not provided 2018-06-18 criteria provided, single submitter clinical testing The CFTR c.3095A>G; p.Tyr1032Cys variant (rs144055758) is reported in individuals with atypical cystic fibrosis (i.e. monosymptomatic disease) when in combination with a severe pathogenic variant (Dork 1997, Leonardi 2013, Ratbi 2007, Ren 2011). This variant has varying clinical consequences and is commonly associated with pancreatic sufficiency (CFTR2 database). It is reported as pathogenic or likely pathogenic in ClinVar (Variation ID: 35861), and is found in the general population at a low overall allele frequency of 0.002% (4/245758 alleles) in the Genome Aggregation Database. The tyrosine at codon 1032 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered pathogenic and likely to be a mild pathogenic variant. REFERENCES CFTR2 database: https://www.cftr2.org Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 Sep;100(3-4):365-77. Leonardi S et al. Early acute pancreatitis in a child with compound heterozygosis F508/R1438W/Y1032C cystic fibrosis: a case report. J Med Case Rep. 2013 Jul 24;7:188. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007 May;22(5):1285-91 Ren CL et al. Clinical outcomes in infants with cystic fibrosis transmembrane conductance regulator (CFTR) related metabolic syndrome. Pediatr Pulmonol. 2011 Nov;46(11):1079-84.
Eurofins Ntd Llc (ga) RCV000591587 SCV000700725 likely pathogenic not provided 2018-06-11 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000029516 SCV000916185 pathogenic Cystic fibrosis 2018-09-06 criteria provided, single submitter clinical testing The CFTR c.3095A>G (p.Tyr1032Cys) missense variant has been reported in four probands in seven different studies (Dörk et al. 1997; Corbetta et al. 2002; Padoan et al. 2006; Ratbi et al. 2007; Seia et al. 2009; Ren et al. 2011; Leonardi et al. 2013). The p.Tyr1032Cys variant was commonly reported in combination with the well-described severe pathogenic variant, p.Phe508del. However, only two of the seven probands had a clearly positive chloride sweat test and would be considered to have classic CF (Dörk et al. 1997; Seia et al. 2009). The p.Tyr1032Cys variant is associated with a mild phenotype (Leonardi et al. 2013). The p.Tyr1032Cys variant presented with various atypical CF phenotypes - persistent hypertrypsinogenaemia and a borderline chloride sweat test, acute pancreatitis at age six with a borderline chloride sweat test, and congenital bilateral absence of the vas deferens (CBAVD) and recurrent bronchitis (Dörk et al. 1997, Padoan et al. 2006, Ratbi et al. 2007; Seia et al. 2009; Ren et al. 2011; Leonardi et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.000036 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Tyr1032Cys variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics RCV001004290 SCV001163166 likely pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009474 SCV001169569 pathogenic CFTR-related disorder 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV000029516 SCV001179821 likely pathogenic Cystic fibrosis 2024-08-22 criteria provided, single submitter clinical testing The p.Y1032C variant (also known as c.3095A>G), located in coding exon 19 of the CFTR gene, results from an A to G substitution at nucleotide position 3095. The tyrosine at codon 1032 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was described in 2 individuals in conjunction with p.F508del (phase unknown); one individual had a positive newborn screen and indeterminate sweat chloride levels while the other had congenital bilateral absence of the vas deferens (CBAVD) and recurrent bronchitis (D&ouml;rk T et al. Hum. Genet., 1997 Sep;100:365-77; Ren CL et al. Pediatr. Pulmonol., 2011 Nov;46:1079-84). In a Caucasian female who presented with a positive newborn screen, borderline sweat tests, and pancreatic sufficiency who went on to develop acute pancreatitis, this variant was in trans with p.F508del and p.R1438W (Leonardi S et al. J Med Case Rep, 2013 Jul;7:188). In CFBE cells, this variant showed reduced CFTR function compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077; Han ST et al. JCI Insight, 2018 Jul;3(14):pii 121159). The p.Y1032C alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000029516 SCV001577665 pathogenic Cystic fibrosis 2025-01-13 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1032 of the CFTR protein (p.Tyr1032Cys). This variant is present in population databases (rs144055758, gnomAD 0.004%). This missense change has been observed in individuals with congenital absence of the vas deferens or cystic fibrosis (PMID: 9272157, 17329263, 19406970, 21520337, 23883480). ClinVar contains an entry for this variant (Variation ID: 35861). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000591587 SCV001714242 pathogenic not provided 2022-09-20 criteria provided, single submitter clinical testing PM2, PM3, PS3
Institute of Reproductive Genetics, University of Münster RCV001642235 SCV001860332 pathogenic Obstructive azoospermia 2022-03-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000591587 SCV002047126 likely pathogenic not provided 2023-12-11 criteria provided, single submitter clinical testing In the published literature, the variant has been reported in individuals affected with Cystic Fibrosis or Cystic Fibrosis related disorders (CFRD) in the published literature (PMIDs: 30888834 (2019), 27171515 (2016), 26277102 (2015), 25910067 (2015), 21538969 (2011), 21520337 (2011), 19406970 (2009)). In addition, this variant has been shown to affect CFTR chloride conductance function (PMIDs: 30046002 (2018), 29805046 (2018)). The frequency of this variant in the general population, 0.000026 (3/113458 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
GeneDx RCV000591587 SCV002577129 likely pathogenic not provided 2022-09-29 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect (Han 2018, Raraigh 2018); Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); This variant is associated with the following publications: (PMID: 12133923, 28603918, 9272157, 27171515, 30046002, 11883825, 16801189, 19318035, 30888834, 21538969, 17407489, 21520337, 29805046, 17329263, 23883480, 35523714, 35451201, Tosco[letter]2022, 35913788)
Baylor Genetics RCV003473138 SCV004213327 pathogenic Bronchiectasis with or without elevated sweat chloride 1 2024-01-16 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005042092 SCV005666402 pathogenic Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation 2024-03-13 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000029516 SCV002507385 uncertain significance Cystic fibrosis 2021-03-19 flagged submission clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001009474 SCV002507471 pathogenic CFTR-related disorder 2021-03-19 no assertion criteria provided clinical testing
Baylor Genetics RCV000029516 SCV002583261 pathogenic Cystic fibrosis no assertion criteria provided clinical testing

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