Submissions for variant NM_024570.4(RNASEH2B):c.488C>T (p.Thr163Ile)

gnomAD frequency: 0.00001  dbSNP: rs79310911

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000805861	SCV000945834	pathogenic	Aicardi-Goutieres syndrome 2	2024-02-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 163 of the RNASEH2B protein (p.Thr163Ile). This variant is present in population databases (rs79310911, gnomAD 0.003%). This missense change has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 16845400). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 650668). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RNASEH2B protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RNASEH2B function (PMID: 25274781). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000805861	SCV005329604	likely pathogenic	Aicardi-Goutieres syndrome 2	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.488C>T(p.Thr163Ile) in RNASEH2B gene has been reported previously in compound heterozygous state in individuals with Aicardi-Goutières syndrome (Crow YJ, et al., 2006, Pizzi S, et al., 2015). Experimental evidence suggests that this mutation along with another mutation p.(Ala177Thr) leads to reduced stability and cellular levels of RNase H2, leading to genome instability and fork stalling (Garau J, et al., 2019). However, additional details are required to prove its pathogenicity. The c.488C>T variant is reported with 0.0004% allele frequency in gnomAD Exomes. The amino acid Threonine at position 163 is changed to a Isoleucine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic. Multiple lines of computational evidence (Polyphen, SIFT and Mutation Taster) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Thr163Ile in RNASEH2B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.