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

gnomAD frequency: 0.00806  dbSNP: rs74737358

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000885048	SCV001028471	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000000277	SCV001136327	benign	Xeroderma pigmentosum, group C	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122346	SCV001363337	benign	not specified	2022-02-18	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 35 fold of the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.00071), 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 (example, Bonache_2018, Li_1993, Martin-Morales_2018, Maxwell_2016, Pugh_2019, Ramirez-Calvo_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Xeroderma Pigmentosum. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example, BernardesdeJesus_2008, Bidon_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000885048	SCV001835975	benign	not provided	2019-12-18	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 18955168, 8298653, 25333069, 17079196, 29973595, 30516811, 30675318, 31816862, 24728327, 18809580, 30256826, 27153395)
Sema4, Sema4	RCV002257356	SCV002537469	benign	Xeroderma pigmentosum	2020-03-26	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000885048	SCV004149240	benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	XPC: BP4, BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003904788	SCV004720634	benign	XPC-related condition	2021-04-10	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.