Submissions for variant NM_032193.4(RNASEH2C):c.247G>A (p.Val83Met)

dbSNP: rs772757667

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000788585	SCV000927742	uncertain significance	not provided	2018-06-11	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272354	SCV002557176	likely pathogenic	Aicardi-Goutieres syndrome 3	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Aicardi-Goutieres syndrome 3 (MIM#610329). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2 highest allele count: 3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ribonuclease H2 non-catalytic subunit domian (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has previously been classified as a VUS by a clinical laboratory in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.205C>T;p.Arg69Trp) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003411732	SCV004112333	likely pathogenic	RNASEH2C-related disorder	2024-04-25	no assertion criteria provided	clinical testing	The RNASEH2C c.247G>A variant is predicted to result in the amino acid substitution p.Val83Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in ClinVar by an outside lab as occurring in trans to a second pathogenic RNASEH2C in a patient with Aicardi-Goutieres syndrome (https://www.ncbi.nlm.nih.gov/clinvar/variation/636680/). At PreventionGenetics, we have observed the c.247G>A variant in trans with a second RNASEH2C variant in a patient with a clinical diagnosis of Aicardi-Goutieres syndrome (internal data). A different missense substitution affecting this amino acid has been reported, homozygous, in a patient with Aicardi-Goutieres syndrome (p.Val83Ala; Boulanger et al. 2021. PubMed ID: 33471103). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic.