ClinVar Miner

Submissions for variant NM_000400.4(ERCC2):c.2141_2148del (p.Val714fs)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002283407 SCV002571986 likely pathogenic Xeroderma pigmentosum 2022-08-12 criteria provided, single submitter clinical testing Variant summary: ERCC2 c.2141_2148delTCCAGGTG (p.Val714GlyfsX57) causes a frameshift which results in an extension of the protein. While this variant is not anticipated to result in nonsense mediated decay, it is predicted to disrupt the last 47 amino acids of the protein and extend the protein by approximately 11 additional amino acid residues. Other protein-extending variants have been reported as pathogenic in ClinVar (variation ID: 1028729). The variant allele was found at a frequency of 4e-06 in 251234 control chromosomes. To our knowledge, no occurrence of c.2141_2148delTCCAGGTG in individuals affected with Xeroderma Pigmentosum and no experimental evidence demonstrating its impact on protein function have been reported. Other variants within the disrupted region of the protein have been classified internally as pathogenic (example: p.Arg722Trp), suggesting this region of the protein is clinically significant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003679090 SCV004425183 pathogenic not provided 2023-01-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ERCC2 protein in which other variant(s) (p.Arg722Trp) have been determined to be pathogenic (PMID: 31282071, 31803976). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1705082). This variant has not been reported in the literature in individuals affected with ERCC2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change results in a frameshift in the ERCC2 gene (p.Val714Glyfs*57). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the ERCC2 protein and extend the protein by 9 additional amino acid residues.

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