ClinVar Miner

Submissions for variant NM_000124.4(ERCC6):c.2551T>C (p.Trp851Arg)

dbSNP: rs368728467
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000195010 SCV000247317 pathogenic Cockayne syndrome type 2 2015-02-24 criteria provided, single submitter clinical testing
Counsyl RCV000675120 SCV000800674 uncertain significance DE SANCTIS-CACCHIONE SYNDROME; Cerebrooculofacioskeletal syndrome 1; Cockayne syndrome type 2 2018-03-20 criteria provided, single submitter clinical testing
Invitae RCV001063571 SCV001228424 pathogenic not provided 2021-11-01 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 851 of the ERCC6 protein (p.Trp851Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ataxia-related phenotypes and/or Cockayne syndrome (PMID: 9443879, 29572252, 29915382, 32557569). ClinVar contains an entry for this variant (Variation ID: 210955). 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 ERCC6 protein function. Experimental studies have shown that this missense change affects ERCC6 function (PMID: 9443879, 20122405, 25820262, 29203878). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844081 SCV002103347 likely pathogenic Cockayne syndrome 2022-02-23 criteria provided, single submitter clinical testing Variant summary: ERCC6 c.2551T>C (p.Trp851Arg) results in a non-conservative amino acid change located in the Helicase, C-terminal domain (IPR001650) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251280 control chromosomes (gnomAD). c.2551T>C has been reported in the literature in individuals affected with Cockayne Syndrome or Cerebellar ataxia (Mallery_1998, Calmels_2018, Sun_2018). These data indicate that the variant may be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in impaired in its ability to associate with chromatin in response to UV irradiation, failed to suppress the increase in 53BP1 and Rif1 damage foci formation in CSB-knockout cells and failed to recruit BRCA1 (Mallery_1998, Lake_2010, Batenburg_2015, Batenburg_2019). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely pathogenic (n=1) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000195010 SCV001132911 pathogenic Cockayne syndrome type 2 2019-08-25 no assertion criteria provided clinical testing

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