Submissions for variant NM_000380.4(XPA):c.323G>A (p.Cys108Tyr)

dbSNP: rs104894131

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000492893	SCV000583159	likely pathogenic	not provided	2015-08-18	criteria provided, single submitter	clinical testing	The C108Y variant in the XPA gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The C108Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C108Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense pathogenic variants in the same residue (C108F) has been reported in the Human Gene Mutation Database in association with xeroderma pigmentosum (Stenson et al., 2014), supporting the functional importance of this region of the protein. The C108Y variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded
Counsyl	RCV000672811	SCV000797955	uncertain significance	Xeroderma pigmentosum group A	2018-02-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000672811	SCV000807586	uncertain significance	Xeroderma pigmentosum group A	2017-09-01	criteria provided, single submitter	clinical testing	This variant was found once in our laboratory homozygous in a 9-year-old male with photosensitivity and learning problems. A similarly affected sister, who also had ataxia, was also homozygous.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586740	SCV005077041	likely pathogenic	Xeroderma pigmentosum	2024-04-22	criteria provided, single submitter	clinical testing	Variant summary: XPA c.323G>A (p.Cys108Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250364 control chromosomes. c.323G>A has been reported in the literature in an individual affected with Xeroderma Pigmentosum and in an affected sibling in the homozygous state (Saleh_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 34374989). ClinVar contains an entry for this variant (Variation ID: 430367). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004586740	SCV005420850	likely pathogenic	Xeroderma pigmentosum	2024-10-04	criteria provided, single submitter	research	PM2,PP3,PP1,PM5
Fulgent Genetics, Fulgent Genetics	RCV000672811	SCV005682093	likely pathogenic	Xeroderma pigmentosum group A	2024-04-26	criteria provided, single submitter	clinical testing