ClinVar Miner

Submissions for variant NM_000124.4(ERCC6):c.2551T>A (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
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000625851 SCV000746419 pathogenic Cockayne syndrome type 2 2017-12-18 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000625851 SCV001429192 pathogenic Cockayne syndrome type 2 2018-11-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001855324 SCV002212796 pathogenic not provided 2021-10-28 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 522698). 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 Cockayne syndrome (PMID: 9443879, 29572252, 32557569). This variant is also known as T2630A. 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). For these reasons, this variant has been classified as Pathogenic.
Department of Animal Biology, Molecular and Human Genetics Lab, University of Tabriz RCV000625851 SCV004814123 pathogenic Cockayne syndrome type 2 2024-04-02 criteria provided, single submitter clinical testing The study of the W851R mutation in the ERCC6 gene is central to understanding the complex pathophysiological processes associated with Cockayne Syndrome (CS). While this variant has been noted in earlier research, its specific impact on the structural integrity of the ERCC6 protein and subsequent changes in its ATPase activity have not been thoroughly examined until now. Our research represents the initial effort to fully analyze the severe consequences of this missense mutation, which appears deceptively benign. Previous studies (Mallery 1998, Laugel 2010, Batenburg 2015) have highlighted the profound negative effects of the W851R mutation on ERCC6 functionality. It has been demonstrated that this mutation results in an ERCC6 protein that lacks DNA-dependent ATPase activity, leading to a disruption in chromatin remodeling and hindering essential repair processes. These findings align with our molecular dynamic simulations, which indicate compromised ATPase and DNA binding functions of the protein.
Fulgent Genetics, Fulgent Genetics RCV005044908 SCV005679862 pathogenic DE SANCTIS-CACCHIONE SYNDROME; Cerebrooculofacioskeletal syndrome 1; Cockayne syndrome type 2; UV-sensitive syndrome 1; Age related macular degeneration 5; Premature ovarian failure 11; Lung cancer 2024-01-11 criteria provided, single submitter clinical testing

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