ClinVar Miner

Submissions for variant NM_005548.3(KARS1):c.717T>G (p.Phe239Leu)

gnomAD frequency: 0.00075  dbSNP: rs117188693
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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, Mass General Brigham Personalized 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, Molecular Genetics and Genomics, 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, Cochlear Implant Center RCV001375254 SCV001572052 likely benign Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing BS1_Strong, BP4_Supporting, BP5_ Supporting
Mayo Clinic Laboratories, Mayo Clinic 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, Academic Medical Center RCV000767138 SCV001926235 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000767138 SCV001964417 uncertain significance not provided no assertion criteria provided clinical testing

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