Submissions for variant NM_018122.5(DARS2):c.788G>A (p.Arg263Gln)

gnomAD frequency: 0.00002  dbSNP: rs121918207

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000001115	SCV000594312	pathogenic	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	2016-02-17	criteria provided, single submitter	clinical testing
GeneDx	RCV002243611	SCV002512899	likely pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing	Identified in the published literature in an individual with LBSL, however a second variant was not identified (Scheper et al., 2007); Functional analysis of recombinant mutant protein showed significantly impaired enzymatic activity compared to wildtype protein (Scheper et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25476837, 33574740, 23216004, 26620921, 30006346, 34503567, 29305884, 17384640, Rathore2017[Abstract], 34631948)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002243611	SCV003523359	likely pathogenic	not provided	2024-03-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 263 of the DARS2 protein (p.Arg263Gln). This variant is present in population databases (rs121918207, gnomAD 0.005%). This missense change has been observed in individuals with clinical features of leukoencephalopathy (PMID: 17384640; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 1060). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DARS2 function (PMID: 17384640, 23216004). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000001115	SCV005907374	likely pathogenic	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	2025-01-21	criteria provided, single submitter	curation	The p.Arg263Gln variant in DARS2 has been reported in 2 individuals, with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (PMID: 17384640, 23216004, Rathore et al. 2017), and has been identified in 0.007% (6/91072) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121918207). 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: 1060) and has been interpreted as pathogenic/likely pathogenic by Genetic Services Laboratory (University of Chicago), OMIM, and GeneDx, and a variant of unknown significance by Invitae. Of the 2 affected individuals, at least 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg263Gln variant is pathogenic (Variation ID: 1057; PMID: 17384640). In vitro functional studies provide some evidence that the p.Arg263Gln variant may slightly impact protein function (PMID: 17384640, 23216004). However, these types of assays may not accurately represent biological function. Computational tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome. ACMG/AMP Criteria applied: PM3, PS3_supporting, PP3_moderate, PM2_supporting (Richards 2015).
OMIM	RCV000001115	SCV000021265	pathogenic	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	2007-04-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000001115	SCV000840287	not provided	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.