rs78635798

Description

Published functional studies demonstrate that R69W is associated with decreased enzyme activity and reduced thermal stability of RNaseH2 (Chon et al., 2009; Reijns et al., 2011); This variant is associated with the following publications: (PMID: 25604658, 31529068, 29239743, 17846997, 21177854, 19034401, 19015152, 26456534, 23322642, 20131292, 16845400, 29150899, 27391121, 24123366, 29302074, 32180488)

This variant is interpreted as a Likely Pathogenic, for Aicardi-Goutieres syndrome 3, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:23322642) (PMID:16845400). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation observed in multiple patients. (PMID:17846997,16845400,20131292,23322642,29150899).

This sequence change replaces arginine with tryptophan at codon 69 of the RNASEH2C protein (p.Arg69Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs78635798, ExAC 0.07%). This missense change has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 16845400, 23322642, 29150899, 29239743). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1260). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RNASEH2C function (PMID: 19015152, 19034401, 31529068). For these reasons, this variant has been classified as Pathogenic.

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001260, PMID:16845400, PS1_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product(PMID: 19015152, 21177854, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.709, PP3_P). A missense variant is a common mechanism associated with Aicardi-Goutieres syndrome 3 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000092, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.