Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000767138 | SCV000569016 | likely benign | not provided | 2020-11-07 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24105373) |
Laboratory for Molecular Medicine, |
RCV000478894 | SCV000711644 | uncertain significance | not specified | 2019-08-27 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The p.Phe267Leu variant in KARS has been identified in the heterozygous state in two individuals with hearing loss (LMM data), but has also been identified in 0.14% (185/129110) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 420262). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. |
ARUP Laboratories, |
RCV000767138 | SCV001472794 | uncertain significance | not provided | 2020-04-04 | criteria provided, single submitter | clinical testing | The KARS c.801T>G; p.Phe267Leu variant (rs117188693) is reported in the literature in a homozygous individual affected with distal hereditary motor neuropathy (Zhao 2014). This variant is found in the non-Finnish European population with an overall allele frequency of 0.14% (185/129110 alleles) in the Genome Aggregation Database. The phenylalanine at codon 267 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, splicing analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor site, although splicing analyses would be required to confirm this. Given the lack of additional clinical and functional data, the significance of the p.Phe267Leu variant is uncertain at this time. References: Zhao H et al. Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy. Eur J Hum Genet. 2014 Jun;22(6):847-50. |
Department of Otolaryngology – Head & Neck Surgery, |
RCV001375254 | SCV001572052 | likely benign | Hearing impairment | 2021-04-12 | criteria provided, single submitter | clinical testing | BS1_Strong, BP4_Supporting, BP5_ Supporting |
Mayo Clinic Laboratories, |
RCV000767138 | SCV001712859 | uncertain significance | not provided | 2020-10-12 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000767138 | SCV002510421 | uncertain significance | not provided | 2022-08-22 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 267 of the KARS protein (p.Phe267Leu). This variant is present in population databases (rs117188693, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 420262). 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 tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. |
Clinical Genetics, |
RCV000767138 | SCV001926235 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000767138 | SCV001964417 | uncertain significance | not provided | no assertion criteria provided | clinical testing |