Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001852644 | SCV002231136 | pathogenic | not provided | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 121 of the TK2 protein (p.His121Asn). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 11687801, 12391347, 16908738, 29602790). It has also been observed to segregate with disease in related individuals. This variant is also known as p.His90Asn. ClinVar contains an entry for this variant (Variation ID: 38986). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects TK2 function (PMID: 12493767, 18446447). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003155045 | SCV003845170 | pathogenic | Mitochondrial DNA depletion syndrome | 2023-02-24 | criteria provided, single submitter | clinical testing | Variant summary: TK2 c.360_361delinsAA (p.His121Asn) results in a conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250910 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (0.00012 vs 0.0011), allowing no conclusion about variant significance. c.360_361delinsAA has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related (Saada_2001, Oskoui_2006, Jou_2019, etc.). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (Saada_2001, Wang_2003). One ClinVar submitter has submitted clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |