Submissions for variant NM_004614.5(TK2):c.415G>A (p.Ala139Thr)

gnomAD frequency: 0.00013  dbSNP: rs138479499

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001927990	SCV002180672	pathogenic	not provided	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 139 of the TK2 protein (p.Ala139Thr). This variant is present in population databases (rs138479499, gnomAD 0.05%). This missense change has been observed in individual(s) with TK2-related myopathy (PMID: 29602790, 30831263, 31060578). ClinVar contains an entry for this variant (Variation ID: 1410181). 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 not expected to disrupt TK2 protein function with a negative predictive value of 80%. This variant disrupts the p.Ala139 amino acid residue in TK2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16504786, 25446393). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002266060	SCV002548335	pathogenic	Mitochondrial DNA depletion syndrome	2024-04-04	criteria provided, single submitter	clinical testing	Variant summary: TK2 c.415G>A (p.Ala139Thr) results in a non-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 6.8e-05 in 251354 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (6.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.415G>A has been reported in the literature as a compound heterozygous genotype in individuals affected with features of Mitochondrial DNA Depletion Syndrome - TK2 Related (e.g. Garone_2018, Nogueira_2019, Dominguez-Gonzalez_2019, Dominguez-Gonzalez_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant located at the same codon (c.416C>T, p.Ala139Val) has been classified as pathogenic by our lab, supporting a critical relevance of this residue to TK2 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 35907766, 31060578, 29602790, 30831263). ClinVar contains an entry for this variant (Variation ID: 1410181). Based on the evidence outlined above, the variant was classified as pathogenic.