ClinVar Miner

Submissions for variant NM_005548.3(KARS1):c.85G>C (p.Ala29Pro)

gnomAD frequency: 0.00005  dbSNP: rs369238198
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002237067 SCV002510400 likely pathogenic not provided 2024-06-22 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 57 of the KARS protein (p.Ala57Pro). This variant is present in population databases (rs369238198, gnomAD 0.006%). This missense change has been observed in individual(s) with KARS-related conditions (PMID: 27243033, 33942428). 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. This variant is also known as p.Ala29Pro. ClinVar contains an entry for this variant (Variation ID: 1682455). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KARS function (PMID: 33942428). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV002237067 SCV002552728 pathogenic not provided 2022-07-19 criteria provided, single submitter clinical testing Published functional studies suggest a damaging effect (Cappuccio et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.85G>C, p.Ala29Pro; This variant is associated with the following publications: (PMID: 27243033, 29615062, 30252186, 33942428, 32730690)
Duke University Health System Sequencing Clinic, Duke University Health System RCV003223432 SCV003918934 likely pathogenic Leukoencephalopathy, progressive, infantile-onset, with or without deafness 2023-04-20 criteria provided, single submitter research
PreventionGenetics, part of Exact Sciences RCV004529106 SCV004108733 uncertain significance KARS1-related disorder 2022-10-14 criteria provided, single submitter clinical testing The KARS1 c.169G>C variant is predicted to result in the amino acid substitution p.Ala57Pro. This variant was reported in the compound heterozygous state in at least two individuals with either epileptic encephalopathy or microcephaly, nystagmus, and intellectual disability (Joshi et al. 2016. PubMed ID: 27243033, reported as p.Ala29Pro; Cope et al. 2020. PubMed ID: 32730690; Cappuccio et al. 2021. PubMed ID: 33942428; Ardissone et al. 2018. PubMed ID: 29615062). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-75675599-C-G). Although we suspect KARS1 c.169G>C (p.Ala57Pro) may be pathogenic, the clinical significance of this variant is currently classified as uncertain due to the absence of conclusive functional and genetic evidence.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.