ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3095A>G (p.Tyr1032Cys) (rs144055758)

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Total submissions: 9
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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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000591587 SCV000700725 likely pathogenic not provided 2018-06-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 disorders 2018-01-29 criteria provided, single submitter curation
Ambry Genetics RCV001018567 SCV001179821 likely pathogenic Inborn genetic diseases 2019-09-09 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.
Invitae RCV000029516 SCV001577665 likely pathogenic Cystic fibrosis 2020-08-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1032 of the CFTR protein (p.Tyr1032Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs144055758, ExAC 0.002%). This variant has been observed in combination with another CFTR variant in several individuals affected 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). This variant has been reported to affect CFTR protein function (PMID: 29805046). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000591587 SCV001714242 likely pathogenic not provided 2021-03-10 criteria provided, single submitter clinical testing PS3, PM3, PP3

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