Submissions for variant NM_004628.5(XPC):c.1177C>T (p.Arg393Trp)

gnomAD frequency: 0.00098  dbSNP: rs121965090

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000998003	SCV001153811	uncertain significance	not provided	2018-12-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001146474	SCV001307221	uncertain significance	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000998003	SCV001714089	uncertain significance	not provided	2020-12-21	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000998003	SCV002009814	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001146474	SCV002030215	uncertain significance	Xeroderma pigmentosum, group C	2021-02-09	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV002257448	SCV002537478	uncertain significance	Xeroderma pigmentosum	2021-11-25	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122342	SCV002548336	uncertain significance	not specified	2022-05-03	criteria provided, single submitter	clinical testing	Variant summary: XPC c.1177C>T (p.Arg393Trp) 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 0.00088 in 249252 control chromosomes. The observed variant frequency is approximately 1.25 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 benign. To our knowledge, no penetrant association of c.1177C>T in individuals affected with Xeroderma Pigmentosum has been reported. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. The authors report a moderate reduction in recruitment of XPC protein to focal DNA damage in an in-vitro system utilizing GFP-tagged XPC plasmids (Qiao_2011). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Fulgent Genetics, Fulgent Genetics	RCV001146474	SCV002782430	uncertain significance	Xeroderma pigmentosum, group C	2022-03-10	criteria provided, single submitter	clinical testing
Invitae	RCV000998003	SCV003270912	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 393 of the XPC protein (p.Arg393Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121965090, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with XPC-related conditions. ClinVar contains an entry for this variant (Variation ID: 135484). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt XPC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000998003	SCV004169806	uncertain significance	not provided	2023-04-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies support a damaging effect: moderate reduction in recruitment of XPC protein to focal DNA damage (Qiao et al., 2011); Observed in individuals with colorectal, bladder, and other cancers, as well as in healthy controls (Qiao et al., 2011; Bodian et al., 2014; Matejcic et al., 2021); This variant is associated with the following publications: (PMID: 21273643, 35530314, 24728327, 33627384)
ITMI	RCV000122342	SCV000086572	not provided	not specified	2013-09-19	no assertion provided	reference population