ClinVar Miner

Submissions for variant NM_002047.4(GARS1):c.2042C>T (p.Pro681Leu)

gnomAD frequency: 0.00001  dbSNP: rs879254346
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000236620 SCV000294295 uncertain significance Charcot-Marie-Tooth disease type 2 2023-08-27 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 681 of the GARS protein (p.Pro681Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 246654). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GARS protein function. 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000660607 SCV000782723 uncertain significance Charcot-Marie-Tooth disease type 2D; Neuronopathy, distal hereditary motor, type 5A 2017-08-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV004020943 SCV002755247 uncertain significance not specified 2022-08-24 criteria provided, single submitter clinical testing The p.P681L variant (also known as c.2042C>T), located in coding exon 16 of the GARS gene, results from a C to T substitution at nucleotide position 2042. The proline at codon 681 is replaced by leucine, an amino acid with similar properties. This variant was identified in one allele in a Charcot-Marie Tooth cohort (Volodarsky M et al. J Med Genet, 2021 04;58:284-288). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV005001025 SCV005626623 uncertain significance not provided 2024-07-09 criteria provided, single submitter clinical testing Reported in a patient with a suspected diagnosis of Charcot-Marie-Tooth disease; however, no further clinical or segregation information was provided (PMID: 32376792); 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; This variant is associated with the following publications: (PMID: 32376792)

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