Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002027348 | SCV002316585 | pathogenic | Combined oxidative phosphorylation defect type 14 | 2025-02-02 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 197 of the FARS2 protein (p.Val197Met). This variant is present in population databases (rs149605576, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive FARS2-related conditions (PMID: 29302074, 31329004, 32774346). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1517423). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FARS2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004782861 | SCV005395353 | uncertain significance | not specified | 2024-09-19 | criteria provided, single submitter | clinical testing | Variant summary: FARS2 c.589G>A (p.Val197Met) results in a conservative amino acid change located in the Phenylalanyl-tRNA synthetase domain (IPR002319) 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 3.7e-05 in 245688 control chromosomes. c.589G>A has been reported in the literature in homozygous or compound heterozygous individuals affected with FARS2-Related Disorders (Hu_2019, Chen_2019, Hotait_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31329004, 32774346, 29302074, 38166857). ClinVar contains an entry for this variant (Variation ID: 1517423). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |