ClinVar Miner

Submissions for variant NM_005548.3(KARS1):c.1493C>T (p.Ala498Val) (rs1415687857)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Diagnostics Services, CSIR - Centre for Cellular and Molecular Biology RCV000856838 SCV000998951 uncertain significance Leukodystrophy; Deafness, autosomal recessive 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 Deafness, autosomal recessive 89 2019-05-28 criteria provided, single submitter clinical testing
Clinica Universidad de La Sabana,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 ( variant / hg19 / NM_001130089.1 (KARS)% 3AA526V)

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