Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genetic Services Laboratory, |
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 | 2023-12-09 | 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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, |
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, |
RCV000195010 | SCV001132911 | pathogenic | Cockayne syndrome type 2 | 2019-08-25 | no assertion criteria provided | clinical testing |