Submissions for variant NM_000380.4(XPA):c.648_649del (p.Lys217fs)

dbSNP: rs1057519018

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865309	SCV002242140	pathogenic	not provided	2023-04-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the XPA protein in which other variant(s) (p.Arg258Tyrfs*5) have been determined to be pathogenic (PMID: 31478152; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 374933). This premature translational stop signal has been observed in individuals with xeroderma pigmentosum (PMID: 25256075, 26884178). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Lys217Glufs*3) in the XPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the XPA protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265751	SCV002547994	pathogenic	Xeroderma pigmentosum	2022-05-16	criteria provided, single submitter	clinical testing	Variant summary: XPA c.648_649delGA (p.Lys217GlufsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251216 control chromosomes. c.648_649delGA has been reported in the literature in multiple individuals affected with Xeroderma Pigmentosum (examples, States_1998, Sun_2015, Fassihi_2016, Zadori_2020, Zhang_2017). These data indicate that the variant is very likely to be associated with disease. Two 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000415712	SCV005055890	pathogenic	Xeroderma pigmentosum group A	2024-02-16	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000415712	SCV000282085	likely pathogenic	Xeroderma pigmentosum group A	2016-03-08	no assertion criteria provided	research	Variant c.648_649 delGA was found to be pathogenic by Mutation Taster online software