Submissions for variant NM_018122.5(DARS2):c.1273G>T (p.Glu425Ter)

dbSNP: rs121918211

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000001120	SCV005200688	uncertain significance	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	2024-09-04	criteria provided, single submitter	curation	The p.Glu425Ter variant in DARS2 has been reported in at least 2 individuals, in the compound heterozygous state, with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (PMID: 17384640, 33977142), and has been identified in 0.0003% (3/1179944) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121918211). Although this variant has been seen in the general population in the heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. However, this variant has only been reported in individuals while also in cis with another pathogenic variant, and therefore it is unknown whether it is disease causing in isolation. This variant has also been reported in ClinVar (Variation ID: 1065) and has been interpreted as Pathogenic by OMIM, Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC), and Joint Genome Diagnostic Labs from Nijmegen and Maastricht (Radboudumc and MUMC+). This nonsense variant leads to a premature termination codon at position 425, which is predicted to lead to a truncated or absent protein. Loss of function of the DARS2 gene is an established disease mechanism in autosomal recessive leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1, PM2_supporting (Richards 2015).
OMIM	RCV000001120	SCV000021270	pathogenic	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	2007-04-01	no assertion criteria provided	literature only
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001794426	SCV002036414	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001794426	SCV002037281	pathogenic	not provided		no assertion criteria provided	clinical testing