ClinVar Miner

Submissions for variant NM_004614.5(TK2):c.562A>G (p.Thr188Ala)

gnomAD frequency: 0.00001  dbSNP: rs281865495
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001852646 SCV002268159 likely pathogenic not provided 2022-05-07 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects TK2 function (PMID: 21937588). 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. ClinVar contains an entry for this variant (Variation ID: 38993). This variant is also known as c.688A>G (p.T230A). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 21937588). 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 present in population databases (rs281865495, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 188 of the TK2 protein (p.Thr188Ala).
Genomenon, Inc, Genomenon, Inc RCV005357240 SCV005911764 pathogenic Mitochondrial disease 2025-04-10 criteria provided, single submitter curation TK2 Thr188Ala (c.562A>G) is a missense variant that changes the amino acid at residue 188 from Threonine to Alanine. It is also described as T230A in the literature. This variant has been observed in a proband affected with mitochondrial disease in the compound heterozygous state, with a pathogenic or likely pathogenic variant confirmed in trans, and was found to segregate with disease in this family (PMID:21937588). Experimental studies have shown that this variant results in a significant reduction of catalytic activity compared to the wild type (PMID:21937588). This variant is not present at a significant frequency in gnomAD. In conclusion, we classify TK2 Thr188Ala (c.562A>G) as a pathogenic variant.
OMIM RCV000239458 SCV000196097 pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 2012-01-01 no assertion criteria provided literature only

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