Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Baylor Genetics | RCV000032251 | SCV000807623 | pathogenic | Mitochondrial DNA depletion syndrome, myopathic form | 2017-09-01 | criteria provided, single submitter | clinical testing | This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant (H121N) in a 16-year-old female with proximal muscle weakness. Heterozygotes are expected to be asymptomatic carriers. |
| Invitae | RCV001380377 | SCV001578415 | pathogenic | not provided | 2024-01-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the TK2 protein (p.Arg183Trp). This variant is present in population databases (rs137886900, gnomAD 0.08%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 15907288, 18819985, 29602790). It has also been observed to segregate with disease in related individuals. This variant is also known as c.673C>T, p.R225W. ClinVar contains an entry for this variant (Variation ID: 38992). 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%. Experimental studies have shown that this missense change affects TK2 function (PMID: 21937588). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg183 amino acid residue in TK2. Other variant(s) that disrupt this residue have been observed in individuals with TK2-related conditions (PMID: 12655576, 12682338, 19265691), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Revvity Omics, |
RCV001380377 | SCV003828073 | pathogenic | not provided | 2022-01-29 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003230374 | SCV003929375 | pathogenic | Mitochondrial DNA depletion syndrome | 2023-04-13 | criteria provided, single submitter | clinical testing | Variant summary: TK2 c.547C>T (p.Arg183Trp) results in a non-conservative amino acid change located in the Deoxynucleoside kinase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251488 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (0.00011 vs 0.0011), allowing no conclusion about variant significance. c.547C>T has been reported in the literature in individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Gene |
RCV000032251 | SCV000055869 | not provided | Mitochondrial DNA depletion syndrome, myopathic form | no assertion provided | literature only | ||
| OMIM | RCV000239457 | SCV000196096 | pathogenic | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 | 2012-01-01 | no assertion criteria provided | literature only |