Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000494549 | SCV000582944 | pathogenic | not provided | 2017-05-18 | criteria provided, single submitter | clinical testing | The R192K variant in the TK2 gene has been reported previously in association with mitochondrial DNA depletion syndrome in an affected individual who was compound heterozygous for the R192K variant and another disease-causing variant (Wang et al., 2005). The R192K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R192K variant is conservative amino acid substitution and occurs at a position that is conserved across species. Functional studies of the R192K variant demonstrated residual enzyme activity of 4% compared to wild type (Wang et al., 2005). We interpret R192K as a pathogenic variant. |
Invitae | RCV000494549 | SCV003442001 | pathogenic | not provided | 2022-08-05 | criteria provided, single submitter | clinical testing | This variant is also known as R161K. This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 15639197, 25948719, 29735374, 31125140). This variant is present in population databases (rs281865496, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 192 of the TK2 protein (p.Arg192Lys). ClinVar contains an entry for this variant (Variation ID: 38994). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg192 amino acid residue in TK2. Other variant(s) that disrupt this residue have been observed in individuals with TK2-related conditions (PMID: 27660820), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects TK2 function (PMID: 15639197). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. |
Gene |
RCV000032253 | SCV000055871 | not provided | Mitochondrial DNA depletion syndrome, myopathic form | no assertion provided | literature only |