ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.4426C>T (p.Gln1476Ter) (rs374705585)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000388068 SCV000331003 pathogenic not provided 2013-08-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000505964 SCV000602994 pathogenic not specified 2016-11-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047135 SCV000697026 pathogenic Cystic fibrosis 2017-05-08 criteria provided, single submitter clinical testing Variant summary: The CFTR c.4426C>T (p.Gln1476X) variant results in a termination codon in the penultimate exon deleting the last four amino acids (Asp-Thr-Arg-Leu). No pathogenic/likely pathogenic truncating variants downstream of this position have been reported in literature, ClinVar and our laboratory and it is outside of some of the commonly known domains (transmembrane domain, ATPase domain and regulator domain) (InterPro). There are no functional studies for this variant as well. Mutation taster predicts a damaging outcome for this variant. This variant was found in 3/120070 control chromosomes including ExAC at a frequency of 0.000025, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). In literature, this variant was found in at least 5 CF patients, 5 CBAVD patients, 3 ICP patients and 3 patients reported to be diagnosed of CFTR-RD. Most patients were known to be compound heterozygotes with another pathogenic variant, primarily with p.Phe508del. In addition, two reported CBAVD patients were found to have elevated sweat chloride implying the diagnosis of CF/NC. Although a nonsense variant, severity of disease associated with this variant is widely reported as mild in literature which can be implicated to its location and resuting functional consequence. One clinical laboratory in ClinVar has classified it as pathogenic. Because CF/NC phenotype has been reported with this variant, and because CBAVD and ICP can also be categorized as manifestation of CF, this variant has been classified as pathogenic with respect to CF/NC phenotype.
Baylor Genetics RCV001004311 SCV001163188 likely pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009479 SCV001169574 pathogenic CFTR-related disorders 2018-01-29 criteria provided, single submitter curation
Invitae RCV000047135 SCV001582233 pathogenic Cystic fibrosis 2020-10-28 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CFTR gene (p.Gln1476*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acids of the CFTR protein. This variant is present in population databases (rs374705585, ExAC 0.01%). This variant has been observed in several individuals affected with cystic fibrosis (PMID: 11938439, 22020151, 25910067, 28544683). ClinVar contains an entry for this variant (Variation ID: 53947). This variant has been reported to affect CFTR protein function (PMID: 30444886). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000047135 SCV001132152 uncertain significance Cystic fibrosis 2018-12-19 no assertion criteria provided clinical testing

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