ClinVar Miner

Submissions for variant NM_005236.3(ERCC4):c.1902A>G (p.Ile634Met)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003788402 SCV004570012 uncertain significance Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q 2023-02-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 634 of the ERCC4 protein (p.Ile634Met). This variant is present in population databases (rs749634352, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ERCC4-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center RCV004784178 SCV005397287 likely pathogenic XFE progeroid syndrome 2021-07-22 criteria provided, single submitter clinical testing This sequence variant is a single nucleotide substitution (A>G) at position 1902 of the coding sequence of the ERCC4 gene that results in an isoleucine to methionine amino acid substitution at residue 634 of XPF, the ERCC4 encoded protein. This is a de novo variant not observed in either of the parental sequences. This variant rare in control population data sets (gnomAD database, 1 of 250954 alleles, 0.0004%) and is absent from online data sets of clinically annotated variants (ClinVar). To our knowledge, this variant has not been observed in individuals with ERCCR4-related disease in the published literature. Multiple bioinformatic tools predict that this isoleucine to methionine amino acid change would be damaging and the isoleucine residue is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been published, to our knowledge. Based on this information, we consider this a likely pathogenic variant. ACMG Criteria: PM2, PP3, PS2

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