ClinVar Miner

Submissions for variant NM_004614.5(TK2):c.310C>T (p.Arg104Cys)

gnomAD frequency: 0.00001  dbSNP: rs1194187379
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics RCV000855771 SCV000998986 likely pathogenic Mitochondrial DNA depletion syndrome, myopathic form 2019-07-17 criteria provided, single submitter clinical testing
GeneDx RCV001772153 SCV002003753 uncertain significance not provided 2021-03-31 criteria provided, single submitter clinical testing 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: 33486010)
Invitae RCV001772153 SCV002175234 likely pathogenic not provided 2023-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 104 of the TK2 protein (p.Arg104Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TK2-related conditions (PMID: 33486010; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 694439). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TK2 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg104 amino acid residue in TK2. Other variant(s) that disrupt this residue have been observed in individuals with TK2-related conditions (PMID: 29602790), which suggests that this may be a clinically significant amino acid residue. 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.
Revvity Omics, Revvity RCV001772153 SCV003825378 uncertain significance not provided 2020-03-16 criteria provided, single submitter clinical testing

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