ClinVar Miner

Submissions for variant NM_001354726.1(XPC):c.-16_-15AT[1] (rs752088918)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589161 SCV000698493 pathogenic Xeroderma pigmentosum 2017-07-20 criteria provided, single submitter clinical testing Variant summary: The c.566_567delAT (p.Tyr189Serfs) variant in XPC gene is a frameshift change predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. These predictions were confirmed by Northern blot analysis that has revealed greatly reduced xeroderma pigmentosum complementation group C mRNA as well as reductions in post-ultraviolet survival rate, unscheduled DNA synthesis, global genome DNA repair deficiency and aborted plasmid host cell reactivation (Slor ,2000). The variant is present in the large control population dataset of ExAC at a low frequency 0.00004 (5/113986 chrs tested), exclusively in individuals of European descent (0.000079; 5/63374 chrs tested) which does not exceed the maximal expected frequency of a pathogenic allele (0.0014) in this gene. The variant of interest has been reported homozygously in at least 3 XP-C patients. The c.566_567delAT is cited as Pathogenic by reputable database/diagnostic center. Taken together, the variant was classified as Pathogenic.
Counsyl RCV000000282 SCV000789545 pathogenic Xeroderma pigmentosum, group C 2017-02-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000000282 SCV000915022 uncertain significance Xeroderma pigmentosum, group C 2018-10-10 criteria provided, single submitter clinical testing The XPC c.566_567delAT (p.Tyr189SerfsTer10) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for xeroderma pigmentosum.
OMIM RCV000000282 SCV000020426 pathogenic Xeroderma pigmentosum, group C 2000-12-01 no assertion criteria provided literature only

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