Submissions for variant NM_006397.3(RNASEH2A):c.556C>T (p.Arg186Trp)

gnomAD frequency: 0.00003  dbSNP: rs77103971

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000610608	SCV000731588	likely pathogenic	Aicardi Goutieres syndrome	2017-03-21	criteria provided, single submitter	clinical testing	The p.Arg186Trp (NM_006397.2 c.556C>T) variant in RNASEH2A has been reported in at least 3 individuals with Aicardi- Goutieres (Rice 2007, Ramantani 2010, and R ice 2013). This variant has been identified in 0.006% (1/17,248) of East Asian c hromosomes by the Genomic Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org/ rs77103971). Although this variant has been seen in the general popula tion, its frequency is consistent with recessive carrier frequency. In vitro fun ctional studies provide supporting evidence that the p.Arg196Trp variant may imp act protein function (Coffin 2011). In summary, this variant meets criteria to b e classified as likely pathogenic for Aicardi- Goutieres syndrome in an autosoma l recessive manner based upon biallelic case observations, supporting functional studies and consistent frequency in the general population.
3billion	RCV000056305	SCV002058288	likely pathogenic	Aicardi-Goutieres syndrome 4	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with RNASEH2A related disorder (ClinVar ID: VCV000066068, PMID:17846997, PS1_P). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000445579, PMID:24300241, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.823, 3CNET: 0.94, PP3_P). A missense variant is a common mechanism associated with Aicardi-Goutieres syndrome 4 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV000056305	SCV003443125	pathogenic	Aicardi-Goutieres syndrome 4	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 186 of the RNASEH2A protein (p.Arg186Trp). This variant is present in population databases (rs77103971, gnomAD 0.006%). This missense change has been observed in individual(s) with Aicardi–Goutieres syndrome (PMID: 20131292, 23592335). 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: 66068). 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) performed at Invitae indicates that this missense variant is expected to disrupt RNASEH2A protein function. Experimental studies have shown that this missense change affects RNASEH2A function (PMID: 21454563). This variant disrupts the p.Arg186 amino acid residue in RNASEH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000610608	SCV003922986	likely pathogenic	Aicardi Goutieres syndrome	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: RNASEH2A c.556C>T (p.Arg186Trp) results in a non-conservative amino acid change located in the Ribonuclease HII/HIII domain (IPR024567) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251490 control chromosomes (gnomAD). c.556C>T has been reported in the literature as a biallelic genotype in individuals affected with Aicardi Goutieres Syndrome (e.g. Ramantani_2010, Rice_2013). These data indicate that the variant may be associated with disease. Experimental evidence evaluating the effects of the variant on protein function showed there was drastic reduction in ribonuclease activity (Coffin_2011). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003894911	SCV004715862	likely pathogenic	RNASEH2A-related condition	2024-01-11	criteria provided, single submitter	clinical testing	The RNASEH2A c.556C>T variant is predicted to result in the amino acid substitution p.Arg186Trp. This variant has been reported in the homozygous or compound heterozygous states in individuals with Aicardi-Goutières syndrome (Rice et al. 2007. PubMed ID: 17846997; Ramantani et al. 2010. PubMed ID: 20131292; Rice et al. 2013. PubMed ID: 23592335). In vitro functional studies suggest this variant affects protein function (Coffin et al. 2011. PubMed ID: 21454563). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic.
OMIM	RCV000056305	SCV000087474	pathogenic	Aicardi-Goutieres syndrome 4	2007-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000056305	SCV000147910	not provided	Aicardi-Goutieres syndrome 4		no assertion provided	literature only