ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate a damaging effect on protein function; specifically, R683W deregulates the early recruitment of TFIIH and NER factors, weakens the interaction with the GTF2H2 subunit, and destabilizes the architecture of TFIIH (Singh et al., 2015; Drane et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7585650, 18510925, 27745642, 11443545, 26884178, 18817897, 22234153, 23221806, 24418926, 15494306, 24252196, 11734544, 9238033, 25431422, 18637129, 22826098, 9101292, 18628313, 25716912, 7920640, 18470933, 18603627, 19934020, 33996357, 31589614, 25620205)

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with xeroderma pigmentosum, group D (MIM#278730). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (17 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated helicase C-terminal domain (PDB). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. An alternate change to glutamine at the same residue has previously been reported as pathogenic in multiple individuals affected with xeroderma pigmentosum (PMID: 26884178). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic, either in a homozygous or compound heterozygous state, in many patients with xeroderma pigmentosum, group D (MIM#278730) (ClinVar, HGMD, PMID: 7585650, PMID: 26884178). (SP) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_000400.3(ERCC2):c.594+2_594+5delTGAG; p(?)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 683 of the ERCC2 protein (p.Arg683Trp). This variant is present in population databases (rs41556519, gnomAD 0.01%). This missense change has been observed in individual(s) with xeroderma pigmentosum (PMID: 7585650, 18637129). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 2125C>T. ClinVar contains an entry for this variant (Variation ID: 16793). 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. This variant disrupts the p.Arg683 amino acid residue in ERCC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9238033, 22826098, 24418926, 29169765). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.