Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Victorian Clinical Genetics Services, |
RCV000578170 | SCV000680029 | likely pathogenic | Hypomyelination with brain stem and spinal cord involvement and leg spasticity | 2017-09-13 | criteria provided, single submitter | clinical testing | A heterozygous missense variant, NM_001349.2(DARS):c.1277T>C, has been identified in exon 14 of 16 of the DARS gene. This substitution creates a major amino acid change of a leucine to serine at position 426, NP_001340.2(DARS):p.(Leu426Ser). The leucine residue at this position has very high conservation (100 vertebrates, UCSC). It is located within an aminoacyl tRNA synthetase class II domain. In-silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0001 (0 homozygotes). The variant has been previously described in a homozygous state as pathogenic in a patient with leukoencephalopathy (Wolf, N. et al., (2015)). Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. |
Invitae | RCV002232469 | SCV002510653 | uncertain significance | not provided | 2022-07-11 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 426 of the DARS protein (p.Leu426Ser). This variant is present in population databases (rs377510027, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of leukodystrophy (PMID: 25527264). ClinVar contains an entry for this variant (Variation ID: 488394). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |