ClinVar Miner

Submissions for variant NM_005236.3(ERCC4):c.1831G>A (p.Gly611Arg)

gnomAD frequency: 0.00001  dbSNP: rs749814308
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Sema4, Sema4 RCV002258697 SCV002537740 uncertain significance Xeroderma pigmentosum 2021-11-29 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235693 SCV003933802 uncertain significance not specified 2023-05-24 criteria provided, single submitter clinical testing Variant summary: ERCC4 c.1831G>A (p.Gly611Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251348 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1831G>A has been reported in the literature as a compound heterozygous genotype in an individual affected with Xeroderma Pigmentosum (Zhou_2017). This report does not provide unequivocal conclusions about association of the variant with Xeroderma Pigmentosum. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27607234). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV003774793 SCV004580200 uncertain significance Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q 2023-09-19 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 611 of the ERCC4 protein (p.Gly611Arg). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERCC4 protein function. ClinVar contains an entry for this variant (Variation ID: 1692878). This missense change has been observed in individual(s) with Xeroderma pigmentosum (PMID: 27607234). This variant is present in population databases (rs749814308, gnomAD 0.004%).

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