Submissions for variant NM_006397.3(RNASEH2A):c.635A>T (p.Asn212Ile)

dbSNP: rs377244188

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000056306	SCV000915817	uncertain significance	Aicardi-Goutieres syndrome 4	2017-04-28	criteria provided, single submitter	clinical testing	The RNASEH2A c.635A>T (p.Asn212Ile) variant has been reported in one individual with Aicardi-Goutieres syndrome in a compound heterozygous state (Rice et al. 2013). The p.Asn212Ile variant was absent from 100 control alleles and is reported at a frequency of 0.0005247 in the European (non-Finnish) population of the Exome Aggregation Consortium. The recombinant p.Asn212Ile variant protein did not have any effect on the catalytic activity although it did cause a small reduction in substrate binding affinity (Coffin et al. 2011). The evidence for this variant is limited. The p.Asn212Ile variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Aicardi-Goutieres syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056306	SCV002307337	uncertain significance	Aicardi-Goutieres syndrome 4	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 212 of the RNASEH2A protein (p.Asn212Ile). This variant is present in population databases (rs377244188, gnomAD 0.08%). This missense change has been observed in individual(s) with Aicardi Goutieres syndrome (PMID: 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: 66069). 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 C15"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RNASEH2A function (PMID: 21454563, 31529068). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700358	SCV005202819	uncertain significance	not specified	2024-07-24	criteria provided, single submitter	clinical testing	Variant summary: RNASEH2A c.635A>T (p.Asn212Ile) results in a non-conservative amino acid change located in the Ribonuclease HII/HIII domain (IPR024567) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00022 in 251418 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RNASEH2A causing Aicardi Goutieres Syndrome, allowing no conclusion about variant significance. c.635A>T has been reported in the literature in at least one compound heterozygous individual affected with Aicardi Goutieres Syndrome and heterozygous in affected individuals without a second variant identified (e.g. Rice_2013, Crow_2015). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant had no significant impact on catalytic activity, although it did cause a small reduction in substrate binding affinity (Coffin_2011, Nishimura_2019). The following publications have been ascertained in the context of this evaluation (PMID: 21454563, 25604658, 31529068, 23592335). ClinVar contains an entry for this variant (Variation ID: 66069). Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM	RCV000056306	SCV000087475	pathogenic	Aicardi-Goutieres syndrome 4	2011-05-13	no assertion criteria provided	literature only