Submissions for variant NM_024570.4(RNASEH2B):c.744A>C (p.Lys248Asn)

gnomAD frequency: 0.00004  dbSNP: rs748144224

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002012474	SCV002280189	uncertain significance	Aicardi-Goutieres syndrome 2	2022-07-21	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 248 of the RNASEH2B protein (p.Lys248Asn). This variant is present in population databases (rs748144224, gnomAD 0.01%). This missense change has been observed in individual(s) with systemic lupus erythematosus (PMID: 25500883). ClinVar contains an entry for this variant (Variation ID: 1492700). 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 C0"). Experimental studies have shown that this missense change affects RNASEH2B function (PMID: 25500883). 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	RCV003235650	SCV003934019	uncertain significance	not specified	2023-05-26	criteria provided, single submitter	clinical testing	Variant summary: RNASEH2B c.744A>C (p.Lys248Asn) results in a non-conservative amino acid change in 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 5.2e-05 in 250548 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RNASEH2B causing Aicardi Goutieres Syndrome (5.2e-05 vs 0.00067), allowing no conclusion about variant significance. c.744A>C has been reported in the literature in individuals affected with Systemic Lupus Erythematosus (Gunther_2015). This report does not provide unequivocal conclusions about association of the variant with Aicardi Goutieres Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function showing 20% recombinant enzyme activity, reduced thermal stability compared to wildtype and impaired nuclear localization (Gunther_2015). The following publication have been ascertained in the context of this evaluation (PMID: 25500883). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.