Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Diagnostics Services |
RCV000856838 | SCV000998951 | uncertain significance | Leukodystrophy; Autosomal recessive nonsyndromic hearing loss 89; Global developmental delay | 2019-11-11 | criteria provided, single submitter | clinical testing | The c.1493C>T variant is not present in publicly available databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC) however present in Genome Aggregation Database (gnomAD) and dbSNP at a very low frequency and only in heterozygous state. The variant is not present in our in-house exome database. The variant was also not reported to OMIM, ClinVar and Human Genome Mutation Database (HGMD) in any other affected individuals. In-silico pathogenicity prediction programs like SIFT, Polyphen2, Mutation Taster2, CADD etc. predicted this variant as likely disease causing. Homozygous variations in the KARS1 gene are known to cause autosomal recessive deafness-89 (MIM#613916). Recently, biallelic variations in this gene have also been reported to cause early-onset progressive leukodystrophy (van der Knaap et al. Neurology 2019; 3. Itoh et al. Brain 2019; Sun et al. Neurol Genet 2019). |
| Mendelics | RCV000986181 | SCV001135091 | likely pathogenic | Autosomal recessive nonsyndromic hearing loss 89 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Clinica Universidad de La Sabana, |
RCV001269077 | SCV001442521 | pathogenic | Sensorineural hearing loss disorder; Leukodystrophy; Global developmental delay | 2020-01-30 | criteria provided, single submitter | clinical testing | It is known what is the impact of some mutations in the KARS domain, nonetheless, there are still multiple KARS gene variations with unestablished clinical significance until this day, and even most of those classified as pathogenic, are not supported nor related to phenotypical reports, in fact, Ardissone et al determined that only 27 patients have a phenotype related to a KARS mutation, this, in relation to the fact that there have been reported 120 variations on ClinVar; from which 31 have been classified as pathogenic and 4 with conflicting interpretations (where we found the second variant of our patient: NM_001130089.1:c.1577C>T), which, up until this day its relation with any phenotype was uncertain, being so, it can now be stated that this second variant can now be classified as pathogenic and related to phenotypical characteristics such as leukodystrophy, hearing loss, and developmental delay. In addition, to the fact that a mutation on this specific domain has been classified as deleterious by analyzing it with 16 bioinformatics predictors (https://varsome.com/ variant / hg19 / NM_001130089.1 (KARS)% 3AA526V) |
| Invitae | RCV003558621 | SCV004297033 | pathogenic | not provided | 2023-11-16 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 526 of the KARS protein (p.Ala526Val). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of Leigh syndrome (PMID: 28496994, 34172899). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 694746). 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 KARS protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |