rs76091978

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 76 of the RNASEH2C protein (p.Pro76Leu). This variant is present in population databases (rs76091978, gnomAD 0.006%). This missense change has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 17846997). ClinVar contains an entry for this variant (Variation ID: 806694). 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.

The missense variant p.P76L in RNASEH2C (NM_032193.4) has been previously reported in homozygous form in affected individual (Rice G et al). It has been submitted to ClinVar as Likely Pathogenic. The p.P76L variant is observed in 1/18,382 (0.0054%) alleles from individuals of East Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.In silico predictios are contradictory: SIFT- Tolerated, Polyphen-Damaging and the residue is conserved across species. For these reasons, this variant has been classified as Likely Pathogenic.