Submissions for variant NM_024570.4(RNASEH2B):c.787A>G (p.Thr263Ala)

gnomAD frequency: 0.00043  dbSNP: rs150363383

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000310729	SCV000339813	uncertain significance	not provided	2016-03-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000690624	SCV000384597	uncertain significance	Aicardi-Goutieres syndrome 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690624	SCV000818321	uncertain significance	Aicardi-Goutieres syndrome 2	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 263 of the RNASEH2B protein (p.Thr263Ala). This variant is present in population databases (rs150363383, gnomAD 0.07%). This missense change has been observed in individual(s) with Aicardi Goutières syndrome (PMID: 24183309). ClinVar contains an entry for this variant (Variation ID: 286394). 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. 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	RCV001844113	SCV002103986	uncertain significance	not specified	2022-02-18	criteria provided, single submitter	clinical testing	Variant summary: RNASEH2B c.787A>G (p.Thr263Ala) 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 0.00032 in 250682 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RNASEH2B causing Aicardi Goutieres Syndrome (0.00032 vs 0.00067), allowing no conclusion about variant significance. c.787A>G has been reported in the literature in an individual affected with Aicardi Goutieres Syndrome (Rice_2013). This report does not provide unequivocal conclusions about association of the variant with Aicardi Goutieres Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000690624	SCV002788971	uncertain significance	Aicardi-Goutieres syndrome 2	2022-04-15	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000310729	SCV001963380	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000310729	SCV001967440	uncertain significance	not provided		no assertion criteria provided	clinical testing