ClinVar Miner

Submissions for variant NM_000123.4(ERCC5):c.2375C>T (p.Ala792Val) (rs121434571)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000018035 SCV000914609 uncertain significance Xeroderma pigmentosum, group G 2018-12-11 criteria provided, single submitter clinical testing The ERCC5 c.2375C>T (p.Ala792Val) missense variant has been reported in at least two studies in which it is found in a compound heterozygous state in two affected siblings with xeroderma pigmentosum, presenting with a mild phenotype (Nouspikel et al. 1994; Nouspikel et al. 1997). Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies showed that lymphoblasts derived from the patients have low levels of DNA synthesis after UV treatment suggesting the variant affects global nucleotide excision repair (Nouspikel et al. 1997). The p.Ala792Val variant was shown to abolish endonuclease activity under certain conditions except on stimulation with manganese ions, which showed weak but measurable activity. A low but detectable endonuclease activity permits removal of some DNA damage and suggests some residual repair capacity which may account for the mild phenotype observed in the patients (Constantinou et al. 1999). Ito et al. (2007) demonstrated that the p.Ala792Val variant is able to form a stable complex with TFIIH. However, Constantinou et al. (1999) report that the variant protein does not stay firmly bound in the repair complex. The Ala792 residue is located in a highly conserved region of the protein. Based on the collective evidence, the p.Ala792Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for xeroderma pigmentosum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000018035 SCV000038314 pathogenic Xeroderma pigmentosum, group G 2007-04-27 no assertion criteria provided literature only

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