Submissions for variant NM_006397.3(RNASEH2A):c.557G>A (p.Arg186Gln)

dbSNP: rs753679297

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514532	SCV000610099	likely pathogenic	not provided	2017-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763423	SCV000894181	likely pathogenic	Aicardi-Goutieres syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000763423	SCV001523640	pathogenic	Aicardi-Goutieres syndrome 4	2020-02-12	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000514532	SCV001802351	pathogenic	not provided	2022-10-07	criteria provided, single submitter	clinical testing	Observed with a second RNASEH2A variant, phase unknown, in an individual with Aicardi-Goutieres syndrome (Abe et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29239743, 34374989, 31130284, 24300241, 36065636)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000763423	SCV002280740	pathogenic	Aicardi-Goutieres syndrome 4	2024-02-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 186 of the RNASEH2A protein (p.Arg186Gln). This variant is present in population databases (rs753679297, gnomAD 0.0009%). This missense change has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 24300241, 29239743). ClinVar contains an entry for this variant (Variation ID: 445579). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002524980	SCV003599564	pathogenic	Inborn genetic diseases	2022-03-02	criteria provided, single submitter	clinical testing	The c.557G>A (p.R186Q) alteration is located in exon 6 (coding exon 6) of the RNASEH2A gene. This alteration results from a G to A substitution at nucleotide position 557, causing the arginine (R) at amino acid position 186 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (1/251488) total alleles studied. This variant has been reported in the homozygous and compound heterozygous state in patients with features of Aicardi-Gouti&egrave;res syndrome (Abe, 2014; Al Mutairi, 2018; Monies, 2017; Monies, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000763423	SCV004013950	pathogenic	Aicardi-Goutieres syndrome 4	2022-11-04	criteria provided, single submitter	clinical testing	PM2, PM5, PP3, PP5
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000763423	SCV004801155	pathogenic	Aicardi-Goutieres syndrome 4	2024-03-14	criteria provided, single submitter	research
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000763423	SCV005420569	likely pathogenic	Aicardi-Goutieres syndrome 4	2024-10-04	criteria provided, single submitter	research	PM3(strong),PM2,PP3,PP1,PM5
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000763423	SCV001133033	pathogenic	Aicardi-Goutieres syndrome 4	2019-09-26	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000514532	SCV001957294	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000514532	SCV001972951	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751576	SCV005357268	pathogenic	RNASEH2A-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The RNASEH2A c.557G>A variant is predicted to result in the amino acid substitution p.Arg186Gln. This variant has been reported many times in both the homozygous and compound heterozygous states in individuals with Aicardi-Goutieres syndrome (see for examples, Abe et al. 2014. PubMed ID: 24300241; Al Mutairi et al. 2017. PubMed ID: 29239743; Table S1, Monies et al. 2019. PubMed ID: 31130284; Saleh et al. 2021. PubMed ID: 34374989). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/445579/). Given the evidence, we interpret this variant as pathogenic.