rs78464826

Description

The P151S variant in the RNASEH2C gene has been reported previously multiples times in individualswith a clinical diagnosis of AGS (Rice et al., 2007). The P151S substitution was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. The P151S variantis a non-conservative amino acid substitution, which is likely to impact secondary protein structure as theseresidues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that isconserved across species. In silico analysis is inconsistent in its predictions as to whether or not thevariant is damaging to the protein structure/function. We interpret P151S as a pathogenic variant.

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 151 of the RNASEH2C protein (p.Pro151Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Aicardi-Goutieres syndrome (PMID: 17846997, 30315573, 32404165). ClinVar contains an entry for this variant (Variation ID: 419543). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.