Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000519291 | SCV000617279 | likely pathogenic | not provided | 2024-03-14 | 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: 25215937, 24516753, 23932787, 29735374, 29602790, 33087887, 18508266, 30183064) |
| Fulgent Genetics, |
RCV000762978 | SCV000893422 | pathogenic | Mitochondrial DNA depletion syndrome, myopathic form; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000519291 | SCV002236178 | pathogenic | not provided | 2024-11-06 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 58 of the TK2 protein (p.Asn58Ser). This variant is present in population databases (rs138439950, gnomAD 0.02%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 18508266, 29735374). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.N100S. ClinVar contains an entry for this variant (Variation ID: 38978). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TK2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004782026 | SCV005394963 | pathogenic | Mitochondrial DNA depletion syndrome | 2024-09-11 | criteria provided, single submitter | clinical testing | Variant summary: TK2 c.173A>G (p.Asn58Ser), also known as N100S, results in a conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251478 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (4.4e-05 vs 0.0011). c.173A>G has been reported in the literature in the homozygous or presumed compound heterozygous state in multiple individuals affected with clinical features of Mitochondrial DNA Depletion Syndrome - TK2 Related (example, Garone_2018, Wang_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence suggesting disturbed ribonucleotide incorporation ratios in mitochondrial DNA in a patient cell line, however, does not allow clear conclusions about the variant effect (example, Berglund_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28207748, 29602790, 29735374). ClinVar contains an entry for this variant (Variation ID: 38978). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Al Jalila Children’s Genomics Center, |
RCV004798750 | SCV005420469 | likely pathogenic | Mitochondrial DNA depletion syndrome 2, myopathic form | 2024-10-04 | criteria provided, single submitter | research | PM3(strong),PM2,PP3,PM1,PP2 |