Submissions for variant NM_018122.5(DARS2):c.172C>G (p.Arg58Gly)

gnomAD frequency: 0.00003  dbSNP: rs375700548

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001548762	SCV002557491	pathogenic	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL, MIM#611105). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 7 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 4 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated anti-codon binding domain (PMID:26620921, PMID: 30006346). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with LBSL (PMID:24566671, PMID:26327357, PMID:33977142). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.771-270_1128+1410del) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV002568303	SCV003523356	pathogenic	not provided	2023-03-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg58 amino acid residue in DARS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects DARS2 function (PMID: 23216004). 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. ClinVar contains an entry for this variant (Variation ID: 1188834). This missense change has been observed in individual(s) with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (PMID: 24566671, 26327357, 33977142). 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 (rs375700548, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 58 of the DARS2 protein (p.Arg58Gly).
Baylor Genetics	RCV001548762	SCV003836439	pathogenic	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	2022-04-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001548762	SCV004048867	pathogenic	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	2023-04-11	criteria provided, single submitter	clinical testing
Gene Discovery Core-Manton Center, Boston Children's Hospital	RCV001548762	SCV001768724	likely pathogenic	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	2020-02-14	no assertion criteria provided	research	This variant is interpretted as Likely Pathogenic for observed Leukoencephalopathy, brain & spine involvement, lactate elevation; Austomal Recessive. PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 - For recessive disorders, detected in trans with a pathogenic variant. PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease. PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation (PMID: 23216004, PMID: 26327357)