ClinVar

Description

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