ClinVar Miner

Submissions for variant NM_002047.4(GARS1):c.305A>G (p.Lys102Arg)

gnomAD frequency: 0.00003  dbSNP: rs369224847
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236202 SCV000292979 uncertain significance not provided 2025-02-18 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
3billion, Medical Genetics RCV001808665 SCV002058507 uncertain significance Charcot-Marie-Tooth disease type 2D 2022-01-03 criteria provided, single submitter clinical testing It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000011, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.717, PP3_P). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV002229802 SCV002508583 uncertain significance Charcot-Marie-Tooth disease type 2 2024-03-27 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 102 of the GARS protein (p.Lys102Arg). This variant is present in population databases (rs369224847, gnomAD 0.006%). 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: 245830). 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 80%. 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.

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