Submissions for variant NM_000380.4(XPA):c.619C>T (p.Arg207Ter)

gnomAD frequency: 0.00002  dbSNP: rs104894133

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657642	SCV000779387	pathogenic	not provided	2018-05-18	criteria provided, single submitter	clinical testing	The R207X pathogenic variant in the XPA gene has been reported previously either in the homozygous state or in combination with another XPA variant in multiple individuals with xeroderma pigmentosum (Satokata et al., 1992; Messaoud et al., 2012; Santiago et al., 2015; Zhang et al., 2017). This variant is predicted to cause loss of normal protein function through protein truncation. Functional studies demonstrated that R207X is associated with impaired function of the XPA protein as a processivity factor (Bartels et al., 2007). The R207X variant is observed in 6/245,910 (0.0002%) alleles in large population cohorts (Lek et al., 2016). We interpret R207X as a pathogenic variant.
Counsyl	RCV000001051	SCV000795241	pathogenic	Xeroderma pigmentosum group A	2017-11-02	criteria provided, single submitter	clinical testing
Medical Molecular Genetics Department, National Research Center	RCV000001051	SCV001335297	pathogenic	Xeroderma pigmentosum group A	2015-12-01	criteria provided, single submitter	research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000657642	SCV001480097	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420782	SCV001623142	pathogenic	Xeroderma pigmentosum	2021-05-09	criteria provided, single submitter	clinical testing	Variant summary: XPA c.619C>T (p.Arg207X) 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 2.4e-05 in 251098 control chromosomes. c.619C>T has been reported in the literature in multiple individuals affected with Xeroderma Pigmentosum (example, Satokata_1992, Messaoud_2012, Zhang_2017, Salomao_2018). These data indicate that the variant is very likely to be associated with disease. Four 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657642	SCV002242897	pathogenic	not provided	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg207*) in the XPA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in XPA are known to be pathogenic (PMID: 27607234). This variant is present in population databases (rs104894133, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosum (PMID: 1372102, 9671271). ClinVar contains an entry for this variant (Variation ID: 996). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000001051	SCV002776876	pathogenic	Xeroderma pigmentosum group A	2021-12-14	criteria provided, single submitter	clinical testing
3billion	RCV000001051	SCV003841376	pathogenic	Xeroderma pigmentosum group A	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000000996 / PMID: 1372102). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000001051	SCV004206955	pathogenic	Xeroderma pigmentosum group A	2023-11-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000001051	SCV005016544	pathogenic	Xeroderma pigmentosum group A	2024-03-14	criteria provided, single submitter	clinical testing
OMIM	RCV000001051	SCV000021201	pathogenic	Xeroderma pigmentosum group A	1992-03-01	no assertion criteria provided	literature only