Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | 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, |
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 | RCV002461039 | SCV002755247 | uncertain significance | Inborn genetic diseases | 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. |