ClinVar Miner

Submissions for variant NM_002047.4(GARS1):c.1960A>G (p.Ile654Val)

gnomAD frequency: 0.00001  dbSNP: rs1406586832
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002238470 SCV002508377 uncertain significance Charcot-Marie-Tooth disease type 2 2023-11-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 654 of the GARS protein (p.Ile654Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with GARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1680958). 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 not expected to disrupt GARS protein function with a negative predictive value of 95%. 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 RCV004690271 SCV005185559 uncertain significance not specified 2024-05-06 criteria provided, single submitter clinical testing Variant summary: GARS1 c.1960A>G (p.Ile654Val) results in a conservative amino acid change located in the Anticodon-binding domain (IPR004154) 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 7.1e-06 in 280912 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1960A>G in individuals affected with GARS1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1680958). Based on the evidence outlined above, the variant was classified as uncertain significance.

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