ClinVar Miner

Submissions for variant NM_004628.5(XPC):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00001  dbSNP: rs763678756
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666438 SCV000790730 likely pathogenic Xeroderma pigmentosum, group C 2017-04-06 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000666438 SCV001311948 uncertain significance Xeroderma pigmentosum, group C 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory 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, this variant 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, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001861752 SCV002114693 pathogenic not provided 2023-12-15 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the XPC mRNA. The next in-frame methionine is located at codon 118. This variant is present in population databases (rs763678756, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with xeroderma pigmentosum (PMID: 18955168). ClinVar contains an entry for this variant (Variation ID: 551388). Studies have shown that disruption of the initiator codon alters XPC gene expression (PMID: 18955168). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002509495 SCV002819292 likely pathogenic Xeroderma pigmentosum 2022-12-06 criteria provided, single submitter clinical testing Variant summary: XPC c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met118) is located in the encoded protein. An activation of potential downstream translation at this initiation site would result in a shortened protein missing the first 117 amino acids from the protein sequence. Two of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 247852 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in XPC causing Xeroderma Pigmentosum (5.2e-05 vs 0.00071), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1A>G in individuals affected with Xeroderma Pigmentosum and no experimental evidence demonstrating its impact on protein function have been reported. However, another variant affecting the ATG initiation codon of XPC, c.2T>G (p.Met1Arg), has been reported in individuals affected with Xeroderma Pigmentosa (Khan_2009). This change has also been shown to severely impair protein expression (Khan_2009), suggesting that variants affecting the start codon of XPC are likely to impact function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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