ClinVar Miner

Submissions for variant NM_000380.3(XPA):c.682C>T (p.Arg228Ter) (rs104894132)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001050 SCV000789455 pathogenic Xeroderma pigmentosum, type 1 2017-02-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000001050 SCV000894457 pathogenic Xeroderma pigmentosum, type 1 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781924 SCV000920350 pathogenic Xeroderma pigmentosum 2018-12-03 criteria provided, single submitter clinical testing Variant summary: XPA c.682C>T (p.Arg228X) 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. The variant allele was found at a frequency of 0.00034 in 276474 control chromosomes (gnomAD). c.682C>T has been reported in the literature in multiple individuals affected with Xeroderma Pigmentosum (Messaoud_2010, Kindil_2017). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000815514 SCV000955973 pathogenic not provided 2018-11-09 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the XPA gene (p.Arg228*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acids of the XPA protein. This variant is present in population databases (rs104894132, ExAC 0.3%). This variant has been observed to be homozygous or in combination with other XPA variants in individuals and families affected with xeroderma pigmentosum (XP) (PMID: 8105686, 26743599, 27413738, 20534089, 29208038, 27607234). This variant has been associated with a milder phenotypic presentation and has been described as a common cause of XP in the North African population (PMID: 29208038, 8105686, 27413738, 20534089). ClinVar contains an entry for this variant (Variation ID: 995). While this variant does not affect the DNA-binding domain and the zinc finger domain of the XPA protein, it is expected to remove the transcription factor II human (TFIIH)-interaction region (residues 226-273) that is required for DNA repair function (PMID: 9671271, 24135642). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001050 SCV000021200 pathogenic Xeroderma pigmentosum, type 1 1995-11-01 no assertion criteria provided literature only
GeneReviews RCV000001050 SCV000320722 pathogenic Xeroderma pigmentosum, type 1 2016-09-26 no assertion criteria provided literature only

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