Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ce |
RCV001200393 | SCV001371340 | pathogenic | not provided | 2020-06-01 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001844271 | SCV002103342 | likely pathogenic | Xeroderma pigmentosum | 2022-02-01 | criteria provided, single submitter | clinical testing | Variant summary: ERCC5 c.2413G>A (p.Gly805Arg) results in a non-conservative amino acid change located in the XPG-I domain (IPR006086) 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 1.2e-05 in 251418 control chromosomes. c.2413G>A has been reported in the literature as a homozygous genotype in at-least one individual affected with Xeroderma Pigmentosum/Cockayne syndrome (example, Schafer_2013). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Schafer_2013, Tsutakawa_2020). The most pronounced variant effect results in abolishment of nucleotide excision repair (NER) activity and impaired interaction with TFIIH subunits XPD and cdk7 thereby impacting transcription activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV001200393 | SCV002300398 | uncertain significance | not provided | 2022-08-10 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects ERCC5 function (PMID: 23370536). ClinVar contains an entry for this variant (Variation ID: 932539). This missense change has been observed in individuals with clinical features of xeroderma pigmentosum/Cockayne Syndrome (PMID: 23370536; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 805 of the ERCC5 protein (p.Gly805Arg). |
| Clinical Genetics Laboratory, |
RCV001200393 | SCV005197832 | likely pathogenic | not provided | 2023-09-15 | criteria provided, single submitter | clinical testing |