ClinVar Miner

Submissions for variant NM_004628.5(XPC):c.1001C>A (p.Pro334His) (rs74737358)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000885048 SCV001028471 benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Mendelics RCV000000277 SCV001136327 uncertain significance Xeroderma pigmentosum, group C 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000000277 SCV001307224 likely benign Xeroderma pigmentosum, group C 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Integrated Genetics/Laboratory Corporation of America RCV000122346 SCV001363337 uncertain significance not specified 2019-10-18 criteria provided, single submitter clinical testing Variant summary: XPC c.1001C>A (p.Pro334His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0026 in 247062 control chromosomes, predominantly at a frequency of 0.025 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma pigmentosum phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1001C>A has been reported in the literature predominantly referencing the same individual, XP1MI, who was a 17 year old African American girl diagnosed with Xeroderma pigmentosum, systemic lupus, and intellectual disability (Li_1993). Since Li_1993's reporting, the variant has been predominantly referred to as pathogenic. The variant has been reported in additional individuals affected with various cancers (Bonache_2018, Martin-Morales_2018, Ramirez-Calvo_2019). The variant has been functionally assessed and was found to "prevent the stimulation of Ogg1 glycosylase because it thwarts the interaction between XPC and Ogg1 (Bernardes de Jesus_2008). 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 VUS-possibly benign.
OMIM RCV000000277 SCV000020421 pathogenic Xeroderma pigmentosum, group C 1993-12-01 no assertion criteria provided literature only
ITMI RCV000122346 SCV000086576 not provided not specified 2013-09-19 no assertion provided reference population
Reproductive Health Research and Development,BGI Genomics RCV000000277 SCV001142327 uncertain significance Xeroderma pigmentosum, group C 2020-01-06 no assertion criteria provided curation NM_004628.4:c.1001C>A (p.Pro334His) was previously reported as P218H. This variant has an allele frequency of 0.026 in African subpopulation in the gnomAD database. It has been reported previously in individuals with Xeroderma Pigmentosum in homozygous state (PMID: 17079196, 17084680). Functional studies show p.Pro334His mutation prevents the stimulation of Ogg1 glycosylase because it thwarts the interaction between XPC and Ogg1 (PMID: 18809580). Benign computational verdict because benign predictions from DEOGEN2, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT vs 1 pathogenic prediction from DANN and the position is not conserved. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BS1, BP4, BP1, PS3, PM3_Supporting.

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