rs137854431

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_004614.5(TK2):c.323C>T(p.Thr108Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

TK2
NM_004614.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 5.48

Variant links:

Genes affected

TK2 (HGNC:11831): (thymidine kinase 2) This gene encodes a deoxyribonucleoside kinase that specifically phosphorylates thymidine, deoxycytidine, and deoxyuridine. The encoded enzyme localizes to the mitochondria and is required for mitochondrial DNA synthesis. Mutations in this gene are associated with a myopathic form of mitochondrial DNA depletion syndrome. Alternate splicing results in multiple transcript variants encoding distinct isoforms, some of which lack transit peptide, so are not localized to mitochondria. [provided by RefSeq, Dec 2012]

TK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a chain Thymidine kinase 2, mitochondrial (size 231) in uniprot entity KITM_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_004614.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

PP5

Variant 16-66531432-G-A is Pathogenic according to our data. Variant chr16-66531432-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TK2	NM_004614.5 link	c.323C>T	p.Thr108Met	missense_variant	Exon 5 of 10	ENST00000544898.6	NP_004605.4	O00142-1Q8IZR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TK2	ENST00000544898.6 link	c.323C>T	p.Thr108Met	missense_variant	Exon 5 of 10	1	NM_004614.5	ENSP00000440898.2		O00142-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251080

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000125

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.000234

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome, myopathic form

Pathogenic:7Other:1

Jan 29, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 11, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TK2 c.323C>T (p.Thr108Met) variant is a missense variant. Across a selection of the available literature, this variant, also described as p.Thr77Met, has been reported in 12 individuals, including seven homozygotes and five compound heterozygotes, from nine families from varying ethnic backgrounds with myopathic mitochondrial DNA depletion syndrome (Mancuso et al. 2002; Mancuso et al. 2003; Wang et al. 2005; Oskoui et al. 2006; Behin et al. 2012; Paradas et al. 2013; Chanprasert et al. 2013; Martin-Hernandez et al. 2017). The clinical symptoms reported among these cases were diverse but generally included a period of normal development after birth followed by onset of myopathy with progression to respiratory failure and early death; however, a few individuals surviving to adulthood and showing slower disease progression are reported. The p.Thr108Met variant was absent from 120 control alleles and is reported at a frequency of 0.000226 in the Latino population of the Genome Aggregation Consortium. Wang et al. (2005) demonstrated that the p.Thr108Met variant enzyme had approximately 3-4% of the activity and approximately 0.5% of the efficiency of the wild type enzyme. Modeling of the TK2 enzyme showed that the Thr108 residue lies in helix four and is involved in active site formation, and an alteration at this residue could disrupt hydrogen bonding (Wang et al. 2005). Based on the collective evidence and application of the ACMG criteria, the p.Thr108Met variant is classified as pathogenic for TK2-related mitochondrial DNA depletion myopathy. -

Jun 19, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 03, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012710, PMID:12391347, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15639197, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.853, 3CNET: 0.91, PP3_P). A missense variant is a common mechanism associated with Mitochondrial DNA depletion syndrome 2 (myopathic type) (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000046, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 09, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_004614:c.323C>T missense variant corresponds to a nucleotide change in a hot spot region in exon 5 of the TK2 gene, which predicts a change at protein level from threonine to methionine at position 108. This variant is found at low frequency in population databases (Genome Aggregation Database) and has multiple reports (ClinVar variation ID: 12710) as pathogenic. Bioinformatic algorithms predict it as deleterious (REVEL=0.85) in coincidence with functional studies described in the literature (PMID: 15639197). For these reasons, we have classified this variant as Pathogenic, according to the following ACMG criteria: PS3, PM1, PM2, PM3, PP3. This variant was found in a homozygous state in the proband. (HPO: 0003202; 0001324; 0003200; 0003737; 0030059). -

Dec 04, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.323C>T (p.Thr108Met) missense variant in the TK2 gene has been previously reported in six affected individuals from three families with autosomal recessive Mitochondrial DNA depletion syndrome, and this variant was shown to segregate with disease within these families (Tritschler et al.,1992; Mancuso et al., 2002; Mancuso et al., 2005; Paradas et al., 2013). Affected individuals have harbored this missense variant in trans with other missense variants (H121N, R192K), an in-frame deletion (K202del), and a nonsense variant (Q125*). This variant is located in exon 5, a known mutational hotspot (Mancuso et al., 2003). This c.323C>T variant also lies within the Î±4 helix of TK2, which is important for enzyme dimerization and nucleoside recognition (Mancuso et al., 2003). Functional studies have shown this variant reduces protein expression, enzymatic activity, and catalytic efficiency of TK2 (Mancuso et al., 2002; Wang et al., 2005; Villarroya et al., 2009). In addition, this variant also leads to reduced enzymatic activity of mitochondrial respiratory chain complexes (complexes I, III, and IV) and reduced cytochrome-c oxidase activity (Mancuso et al., 2002; Mancuso et al., 2003). This variant is absent from two control population databases (Exome Sequencing Project [ESP] and 1000 Genomes) and present at a low frequency in a third control population database (ExAC = 0.009%). Multiple lines of computational evidence suggest a deleterious effect (GERP = 4.97; PolyPhen = 1; SIFT = 0.026), and reputable diagnostic laboratories have reported this variant as pathogenic. Therefore, this collective evidence supports the classification of the c.323C>T (p.Thr108Met) as a recessive Pathogenic variant for Mitochondrial DNA depletion syndrome. -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.323C>T p.Thr108Met in the TK2 gene has been reported previously in a compound heterozygous and homozygous state in individuals affected with mitochondrial DNA depletion syndrome. Functional studies have shown this variant reduces protein expression, enzymatic activity, and catalytic efficiency of TK2 Wang et al., 2005; Mancuso et al., 2003. This variant is reported with the allele frequency 0.004% in the gnomAD and novel in not in any individuals 1000 genome database. It is submitted to ClinVar as Pathogenic. The amino acid Threonine at position 108 is changed to a Methionine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Thr108Met in TK2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 108 of the TK2 protein (p.Thr108Met). This variant is present in population databases (rs137854431, gnomAD 0.02%). This missense change has been observed in individuals with mtDNA depletion syndrome (PMID: 12391347, 12873860, 15639197, 16908738, 22345218, 23303857, 28812460). This variant is also known as T77M. ClinVar contains an entry for this variant (Variation ID: 12710). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TK2 protein function. Experimental studies have shown that this missense change affects TK2 function (PMID: 12391347, 12873860, 15639197, 19265691, 24484525, 28812460). For these reasons, this variant has been classified as Pathogenic. -

May 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found this variant is associated with a significant decrease in enzyme efficiency and catalytic activity compared to wild-type (PMID: 15639197); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(T77M); This variant is associated with the following publications: (PMID: 28217183, 29602790, 16908738, 19265691, 18021809, 12873860, 1734306, 23303857, 26925861, 27839525, 28812460, 29625556, 25948719, 32140910, 31589614, 36344503, 33486010, 32161153, 12391347, 22345218, 15639197, 31060578) -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TK2: PP4:Strong, PM1, PM2, PM3, PS3:Supporting -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3

Pathogenic:1

Jul 01, 2023

DECIPHERD-UDD, Universidad del Desarrollo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mitochondrial DNA depletion syndrome

Pathogenic:1

Feb 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TK2 c.323C>T (p.Thr108Met) 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 4.4e-05 in 251080 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TK2 causing TK2-Related Mitochondrial DNA Depletion Syndrome (4.4e-05 vs 0.0011), allowing no conclusion about variant significance. c.323C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with TK2-Related Mitochondrial DNA Depletion Syndrome (e.g. Wang_2005, Camara_2015). 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 (Wang_2005). The most pronounced variant effect results in <10% of enzyme activity versus the WT protein. The following publications have been ascertained in the context of this evaluation (PMID: 25948719, 15639197). ClinVar contains an entry for this variant (Variation ID: 12710). Based on the evidence outlined above, the variant was classified as pathogenic. -

TK2-related disorder

Pathogenic:1

Jun 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TK2 c.323C>T variant is predicted to result in the amino acid substitution p.Thr108Met. This particular substitution has been shown to lead to an approximately 100-fold decrease in the enzyme efficiency of thymidine kinase 2 (TK2) (defined as “T77M” in Wang et al. 2005. PubMed ID: 15639197). The p.Thr108Met substitution has also been repeatedly reported as “T77M” or “T108M” in patients with mitochondrial DNA depletion syndrome (Mancuso et al. 2003. PubMed ID: 12873860; Mancuso et al. 2002. PubMed ID: 12391347; Oskoui et al. 2006. PubMed ID: 16908738). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

D;.;D;.;.;.;.;D;.;.;.;D;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D;.;D;.;D;D;D;.;D;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.0

M;.;M;.;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.7

.;.;.;.;D;D;D;D;D;.;.;.;.

REVEL

Pathogenic

0.85

Sift

Benign

0.063

.;.;.;.;T;T;T;T;T;.;.;.;.

Sift4G

Uncertain

0.028

D;D;D;D;T;D;D;D;T;D;T;.;.

Polyphen

1.0

D;.;D;.;.;P;.;.;.;.;.;.;.

Vest4

0.84

MVP

0.96

MPC

1.1

ClinPred

0.61

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over