Submissions for variant NM_004628.5(XPC):c.566_567del (p.Tyr189fs)

dbSNP: rs752088918

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589161	SCV000698493	pathogenic	Xeroderma pigmentosum	2017-07-20	criteria provided, single submitter	clinical testing	Variant summary: The c.566_567delAT (p.Tyr189Serfs) variant in XPC gene is a frameshift change predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. These predictions were confirmed by Northern blot analysis that has revealed greatly reduced xeroderma pigmentosum complementation group C mRNA as well as reductions in post-ultraviolet survival rate, unscheduled DNA synthesis, global genome DNA repair deficiency and aborted plasmid host cell reactivation (Slor ,2000). The variant is present in the large control population dataset of ExAC at a low frequency 0.00004 (5/113986 chrs tested), exclusively in individuals of European descent (0.000079; 5/63374 chrs tested) which does not exceed the maximal expected frequency of a pathogenic allele (0.0014) in this gene. The variant of interest has been reported homozygously in at least 3 XP-C patients. The c.566_567delAT is cited as Pathogenic by reputable database/diagnostic center. Taken together, the variant was classified as Pathogenic.
Counsyl	RCV000000282	SCV000789545	pathogenic	Xeroderma pigmentosum, group C	2017-02-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000000282	SCV000915022	uncertain significance	Xeroderma pigmentosum, group C	2018-10-10	criteria provided, single submitter	clinical testing	The XPC c.566_567delAT (p.Tyr189SerfsTer10) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL 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 for this variant, it 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 and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for xeroderma pigmentosum.
Invitae	RCV001062453	SCV001227254	pathogenic	not provided	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr189Serfs*10) in the XPC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in XPC are known to be pathogenic (PMID: 23173980, 25256075). This variant is present in population databases (rs752088918, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosum (PMID: 11121128). It has also been observed to segregate with disease in related individuals. This variant is also known as c.669_670delAT. ClinVar contains an entry for this variant (Variation ID: 258). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000000282	SCV004206972	pathogenic	Xeroderma pigmentosum, group C	2024-03-19	criteria provided, single submitter	clinical testing
OMIM	RCV000000282	SCV000020426	pathogenic	Xeroderma pigmentosum, group C	2000-12-01	no assertion criteria provided	literature only