ClinVar Miner

Submissions for variant NM_020442.6(VARS2):c.2584G>A (p.Glu862Lys)

gnomAD frequency: 0.00011  dbSNP: rs200019717
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001585212 SCV001818568 likely pathogenic not provided 2019-10-08 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001585212 SCV003293406 uncertain significance not provided 2022-11-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 892 of the VARS2 protein (p.Glu892Lys). 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. 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 VARS2 protein function. ClinVar contains an entry for this variant (Variation ID: 1215330). This variant has not been reported in the literature in individuals affected with VARS2-related conditions. This variant is present in population databases (rs200019717, gnomAD 0.02%).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003388030 SCV004099819 uncertain significance not specified 2023-09-13 criteria provided, single submitter clinical testing Variant summary: VARS2 c.2584G>A (p.Glu862Lys) results in a conservative amino acid change located in the Valyl tRNA synthetase, anticodon-binding domain (IPR033705) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.4e-05 in 243994 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2584G>A in individuals affected with Combined Oxidative Phosphorylation Defect Type 20 and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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