Submissions for variant NM_004614.5(TK2):c.388C>T (p.Arg130Trp)

gnomAD frequency: 0.00008  dbSNP: rs281865493

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268843	SCV001448048	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001268843	SCV001783241	pathogenic	not provided	2024-04-16	criteria provided, single submitter	clinical testing	Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 20083405); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R172W); This variant is associated with the following publications: (PMID: 20083405, 18819985, no PMID, 31060578, 29602790, 23230576, 32827528, 34426522, 31589614, 34973561)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001268843	SCV002246003	pathogenic	not provided	2024-04-15	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 130 of the TK2 protein (p.Arg130Trp). This variant is present in population databases (rs281865493, gnomAD 0.08%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 20083405, 29602790). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 38988). 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: 20083405). For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000032247	SCV004809665	pathogenic	Mitochondrial DNA depletion syndrome, myopathic form	2024-04-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055529	SCV005726377	pathogenic	Mitochondrial DNA depletion syndrome	2024-11-13	criteria provided, single submitter	clinical testing	Variant summary: TK2 c.388C>T (p.Arg130Trp) results in a non-conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) 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 7.6e-05 in 251236 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TK2 causing Mitochondrial DNA Depletion Syndrome - TK2 Related (7.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.388C>T has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related (e.g. Lesko_2010, Garone_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <4% of normal activity (Lesko_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20083405, 29602790). ClinVar contains an entry for this variant (Variation ID: 38988). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews	RCV000032247	SCV000055865	not provided	Mitochondrial DNA depletion syndrome, myopathic form		no assertion provided	literature only