Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002035468 | SCV002232965 | pathogenic | not provided | 2021-12-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 expected to disrupt DARS2 protein function. This missense change has been observed in individual(s) with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (PMID: 24566671; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs766714463, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 254 of the DARS2 protein (p.Gly254Ser). |
| Broad Center for Mendelian Genomics, |
RCV005253960 | SCV005907369 | uncertain significance | Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome | 2025-01-21 | criteria provided, single submitter | curation | The p.Gly254Ser variant in DARS2 has been reported, in the compound heterozygous state, in 1 individual with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (PMID: 24566671), and has been identified in 0.005% (3/59988) of Admixed chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs766714463). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1452120), and has been interpreted as Pathogenic by Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly254Ser variant is uncertain. ACMG/AMP Criteria applied: PP3_moderate, PM2_supporting, PM3_supporting (Richard 2015). |