ClinVar Miner

Submissions for variant NM_002047.4(GARS1):c.1171C>T (p.Arg391Cys)

dbSNP: rs370057212
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV001591166 SCV000613377 uncertain significance not provided 2021-04-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000653904 SCV000775794 uncertain significance Charcot-Marie-Tooth disease type 2 2022-06-04 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 391 of the GARS protein (p.Arg391Cys). This variant is present in population databases (rs370057212, gnomAD 0.003%). This missense change has been observed in individual(s) with Charcot Marie Tooth disease (PMID: 24078732). ClinVar contains an entry for this variant (Variation ID: 447371). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
GeneDx RCV001591166 SCV001826166 likely benign not provided 2020-12-22 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26752306, 24078732)
Ambry Genetics RCV004023507 SCV002755184 uncertain significance not specified 2021-05-04 criteria provided, single submitter clinical testing The p.R391C variant (also known as c.1171C>T), located in coding exon 9 of the GARS gene, results from a C to T substitution at nucleotide position 1171. The arginine at codon 391 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in an individual with Charcot-Marie-Tooth (CMT) disease, and in an unaffected control individual in a different CMT disease cohort; however, clinical details were limited (Sivera R et al. Neurology, 2013 Oct;81:1617-25; Lupo V et al. J Mol Diagn, 2016 Mar;18:225-34). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Inherited Neuropathy Consortium RCV000789778 SCV000929162 likely benign Charcot-Marie-Tooth disease no assertion criteria provided literature only
Genesis Genome Database RCV000789778 SCV000999758 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research
Inherited Neuropathy Consortium Ii, University Of Miami RCV003447142 SCV004174567 uncertain significance Charcot-Marie-Tooth disease type 2D 2016-01-06 no assertion criteria provided literature only

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