ClinVar Miner

Submissions for variant NM_005548.3(KARS1):c.797T>C (p.Ile266Thr)

gnomAD frequency: 0.00003  dbSNP: rs762673443
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neurogenetic Laboratory, Second Faculty of Medicine, Charles University RCV001374668 SCV001571594 uncertain significance Autosomal recessive nonsyndromic hearing loss 89 2021-03-30 criteria provided, single submitter clinical testing
GeneDx RCV002469383 SCV002765844 uncertain significance not provided 2022-12-13 criteria provided, single submitter clinical testing Observed with a second variant (phase unknown) in a patient in published literature with congenital hearing loss, abnormality in the white matter on MRI, and adult-onset of progressive neurocognitive decline, hypertonia, seizures, ataxia, and abnormal movement (Sun et al., 2019); Reported with a second variant (phase unknown) in a patient with hearing loss in published literature (Safka Brozkova et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34062854, 31192300)
Labcorp Genetics (formerly Invitae), Labcorp RCV002469383 SCV003519690 uncertain significance not provided 2024-06-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 294 of the KARS protein (p.Ile294Thr). This variant is present in population databases (rs762673443, gnomAD 0.03%). This missense change has been observed in individuals with deafness and/or clinical features of Leigh syndrome (PMID: 31192300, 34062854). ClinVar contains an entry for this variant (Variation ID: 1064651). 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 have shown that this missense change affects KARS function (PMID: 31192300). 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.

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