ClinVar Miner

Submissions for variant NM_004628.5(XPC):c.622-2A>C

gnomAD frequency: 0.00003  dbSNP: rs201940931
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Claritas Genomics RCV000170430 SCV000222867 pathogenic Xeroderma pigmentosum, group C 2010-07-03 criteria provided, single submitter clinical testing
Counsyl RCV000170430 SCV000796229 pathogenic Xeroderma pigmentosum, group C 2017-12-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174681 SCV001337914 pathogenic Xeroderma pigmentosum 2020-01-10 criteria provided, single submitter clinical testing Variant summary: XPC c.622-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: five predict the variant abolishes a 3' acceptor site. This prediction was confirmed by experimental evidence, demonstrating that this variant affects mRNA splicing (Khan_2006). The variant allele was found at a frequency of 1.2e-05 in 247456 control chromosomes (gnomAD). c.622-2A>C has been reported in the literature in individuals affected with Xeroderma pigmentosum (Khan_2006, Rivera-Begeman_2007). These data indicate that the variant may be associated with disease. Publications reported that this variant results in altered mRNA (Khan_2006), decreased mRNA levels (Rivera-Begeman_2007) and the absence of the encoded protein (Khan_2006). 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 pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001205980 SCV001377264 pathogenic not provided 2023-10-22 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the XPC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs201940931, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with xeroderma pigmentosum (PMID: 16081512, 17079196). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 190209). Studies have shown that disruption of this splice site alters XPC gene expression (PMID: 16081512). Studies have shown that disruption of this splice site results in 83 bp insertion of intron 5 and introduces a premature termination codon (PMID: 16081512). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000170430 SCV004207004 pathogenic Xeroderma pigmentosum, group C 2024-02-02 criteria provided, single submitter clinical testing

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