Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
RCV000032238 | SCV000914735 | uncertain significance | Mitochondrial DNA depletion syndrome, myopathic form | 2017-05-05 | criteria provided, single submitter | clinical testing | The TK2 c.191C>T (p.Thr64Met) variant has been reported in at least two studies and is found in two affected siblings with the variant in a compound heterozygous state with a second missense variant (Tulinius et al. 2005; Chanprasert et al. 2013). The siblings were diagnosed with a myopathic form of mitochondrial DNA depletion syndrome, and presented with hypotonia, muscle weakness, and less than 10% mtDNA content in skeletal muscle. The p.Thr64Met variant was absent from 100 control alleles (Tulinius et al. 2005). This variant is reported at a frequency of 0.00003 in the Latino population of the Genome Aggregation Database, but this is based on one allele so the variant is presumed to be rare. The evidence for the p.Thr64Met variant is limited and it is therefore classified as a variant of unknown significance but suspicious for pathogenicity for mitochondrial DNA depletion syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
Invitae | RCV001852643 | SCV002164445 | pathogenic | not provided | 2023-10-08 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 64 of the TK2 protein (p.Thr64Met). This variant is present in population databases (rs281865487, gnomAD 0.003%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 15907288, 33486010). 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. ClinVar contains an entry for this variant (Variation ID: 38979). 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. For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV001852643 | SCV004031792 | likely pathogenic | not provided | 2023-08-30 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); 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: 15907288, 33486010, 29602790) |