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 α4 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.
ClinVar Genomic variation as it relates to human health
NM_004614.5(TK2):c.323C>T (p.Thr108Met)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(14)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004614.5(TK2):c.323C>T (p.Thr108Met)
Variation ID: 12710 Accession: VCV000012710.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16q21 16: 66531432 (GRCh38) [ NCBI UCSC ] 16: 66565335 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 20, 2024 May 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004614.5:c.323C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004605.4:p.Thr108Met missense NM_001172643.1:c.230C>T NP_001166114.1:p.Thr77Met missense NM_001172644.2:c.248C>T NP_001166115.1:p.Thr83Met missense NM_001172645.2:c.269C>T NP_001166116.1:p.Thr90Met missense NM_001271934.2:c.176C>T NP_001258863.1:p.Thr59Met missense NM_001271935.1:c.230C>T NP_001258864.1:p.Thr77Met missense NM_001272050.2:c.32C>T NP_001258979.1:p.Thr11Met missense NR_073520.2:n.1312C>T non-coding transcript variant NC_000016.10:g.66531432G>A NC_000016.9:g.66565335G>A NG_016862.1:g.23981C>T O00142:p.Thr108Met - Protein change
- T108M, T59M, T11M, T90M, T77M, T83M
- Other names
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p.T108M:ACG>ATG
- Canonical SPDI
- NC_000016.10:66531431:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00013
Trans-Omics for Precision Medicine (TOPMed) 0.00023
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| TK2 | - | - |
GRCh38 GRCh37 |
457 | 559 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Oct 9, 2023 | RCV000013547.40 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 1, 2024 | RCV000199738.20 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 1, 2023 | RCV003883499.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 23, 2024 | RCV003993743.1 | |
|
TK2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 14, 2024 | RCV004757106.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Dec 04, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome, myopathic form
Affected status: no
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000538066.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Comment:
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 … (more)
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 α4 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. (less)
|
|
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Pathogenic
(Feb 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001414868.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
This sequence change replaces threonine with methionine at codon 108 of the TK2 protein (p.Thr108Met). The threonine residue is highly conserved and there is a … (more)
This sequence change replaces threonine with methionine at codon 108 of the TK2 protein (p.Thr108Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs137854431, ExAC 0.009%). This variant has been reported in several families and unrelated individuals affected with mtDNA depletion syndrome, both as homozygous or in combination with other heterozygous TK2 variants (PMID: 12391347, 12873860, 15639197, 16908738, 22345218, 23303857, 26925861). It is also known as T77M in the literature. ClinVar contains an entry for this variant (Variation ID: 12710). An experimental study has shown that this missense change results in a dramatic reduction in TK2 activity compared to wild-type protein in vitro (PMID: 15639197). In addition, TK2 activity is markedly reduced in cells from affected individuals with this variant, and there is a noted depletion of mtDNA (PMID: 12391347, 12873860, 19265691, 24484525, 28812460). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000252384.16
First in ClinVar: Oct 11, 2015 Last updated: Sep 16, 2024 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004010494.12
First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024 |
Comment:
TK2: PP4:Strong, PM1, PM2, PM3, PS3:Supporting
Number of individuals with the variant: 2
|
|
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Pathogenic
(Jun 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome, myopathic form
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001520691.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
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Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome, myopathic form
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058407.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Myopathy (present)
|
|
|
Pathogenic
(Sep 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome, myopathic form
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV001423758.2
First in ClinVar: Jul 25, 2020 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jul 01, 2023)
|
criteria provided, single submitter
Method: research
|
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3
Affected status: yes
Allele origin:
maternal
|
DECIPHERD-UDD, Universidad del Desarrollo
Accession: SCV004101825.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
Clinical Features:
Neurodegeneration (present) , Seizure (present) , Brain atrophy (present) , Cardiac arrhythmia (present) , Necrotizing myopathy (present) , Elevated circulating creatine kinase concentration (present) , … (more)
Neurodegeneration (present) , Seizure (present) , Brain atrophy (present) , Cardiac arrhythmia (present) , Necrotizing myopathy (present) , Elevated circulating creatine kinase concentration (present) , Increased circulating lactate concentration (present) , Hyporeflexia (present) , Diaphragmatic weakness (present) , Weak cry (present) , Muscle weakness (present) (less)
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Pathogenic
(Oct 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome, myopathic form
Affected status: yes
Allele origin:
unknown
|
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan
Accession: SCV004231894.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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). (less)
Sex: male
|
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Pathogenic
(Feb 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004814035.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
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 … (more)
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. (less)
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|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome, myopathic form
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005042560.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Abnormality of the nervous system (present)
|
|
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Pathogenic
(Jan 29, 2013)
|
no assertion criteria provided
Method: literature only
|
MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033794.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
Based on the revised protein sequence for TK2 (GenBank NP_004605.4), the mutation designated THR77MET (T77M) and later THR150MET (T150M) is now referred to as THR108MET … (more)
Based on the revised protein sequence for TK2 (GenBank NP_004605.4), the mutation designated THR77MET (T77M) and later THR150MET (T150M) is now referred to as THR108MET (T108M) (Behin et al., 2012). Mancuso et al. (2002) described 2 sibs with mitochondrial DNA depletion syndrome-2 (MTDPS2; 609560) who were compound heterozygous for the previously described H90N mutation (188250.0001) and a novel thr77-to-met (THR77MET) mutation. The proband was normal until 12 months of age when he developed frequent falls and progressive gait impairment, leading to inability to walk by age 26 months. By age 2 years he was unable to stand. He became dependent on mechanical ventilation by 3 years of age and died at 40 months of age. An older sister was similarly affected but with a more slowly evolving course. At age 16 months she began to have frequent falls, limb weakness, and gait abnormality, and by age 4 years she was no longer able to walk. She had elevated serum CK levels and lactic acidosis. In a family originally described by Tritschler et al. (1992) in which 3 sibs had mitochondrial DNA depletion syndrome-2, Mancuso et al. (2003) identified homozygosity for the THR77MET mutation. The patients had 80 to 90% mitochondrial DNA depletion in muscle biopsy specimens, and all died of respiratory failure by age 40 months. The mutation is near the active site, in the alpha-4 helix of the protein, which is important for enzyme dimerization and nucleoside recognition. The authors noted that exon 5 is a hotspot for TK2 mutations. Behin et al. (2012) reported 2 unrelated patients who were homozygous for the T108M mutation but who had had a milder course and slower progression than previously associated with this mutation. One patient had hypotonia since birth, delayed early walking, and proximal muscle weakness in childhood, whereas the other showed early fatigue in childhood; both presented in their early thirties with more significant impairment. Features included waddling gait, distal and proximal muscle weakness, axial weakness, and respiratory insufficiency. One patient was wheelchair-bound and the other could not walk for more than 15 minutes. More variable features included ptosis, hypophonia, and facial weakness. Cognition, hearing, and cardiac function were normal. EMG showed a myogenic pattern, and muscle biopsies showed dystrophic changes consistent with a mitochondrial myopathy, including deficiencies of complexes I, III, and IV. Muscle mtDNA depletion was apparent, with mtDNA levels at about 30% of normal controls. This report expanded the phenotypic spectrum of MTDPS2 to include patients with much slower progression, which may have been due to better preservation of residual muscle mtDNA compared to more severely affected patients. Paradas et al. (2013) reported a 22-year-old man, born of consanguineous parents, with MTDPS2 due to a homozygous T108M mutation. He had normal development until age 24 months, when he showed proximal muscle weakness of the lower limbs resulting in a waddling gait. At age 20, he had a nasal voice and mild proximal arm weakness. After sudden onset of respiratory arrest triggered by pneumonia, he had rapid worsening of the muscle weakness and became wheelchair-bound. He had severe axial and proximal muscle weakness, facial weakness without ptosis, pectoral atrophy, scapular winging, and ankle contractures. He also had significant gynecomastia of unclear etiology. Laboratory studies showed increased serum creatine kinase and normal serum lactate. Muscle samples showed dystrophic features, endomysial fibrosis, abnormally shaped mitochondria, decreased mitochondrial complex I activity (35% of normal), and multiple mtDNA deletions (45% residual mtDNA). Family history revealed a 3-year-old sister who died of respiratory failure due to muscular dystrophy as well as 2 infant deaths in previous generations. The report was notable for significant intrafamilial phenotypic heterogeneity. Functional studies of the T108M variant were not performed. (less)
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Pathogenic
(Jun 14, 2024)
|
no assertion criteria provided
Method: clinical testing
|
TK2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005344697.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
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not provided
(-)
|
no classification provided
Method: literature only
|
Mitochondrial DNA depletion syndrome, myopathic form
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000055859.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2022 |
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Comment:
Comment:
This sequence change replaces threonine with methionine at codon 108 of the TK2 protein (p.Thr108Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs137854431, ExAC 0.009%). This variant has been reported in several families and unrelated individuals affected with mtDNA depletion syndrome, both as homozygous or in combination with other heterozygous TK2 variants (PMID: 12391347, 12873860, 15639197, 16908738, 22345218, 23303857, 26925861). It is also known as T77M in the literature. ClinVar contains an entry for this variant (Variation ID: 12710). An experimental study has shown that this missense change results in a dramatic reduction in TK2 activity compared to wild-type protein in vitro (PMID: 15639197). In addition, TK2 activity is markedly reduced in cells from affected individuals with this variant, and there is a noted depletion of mtDNA (PMID: 12391347, 12873860, 19265691, 24484525, 28812460). For these reasons, this variant has been classified as Pathogenic.
Comment:
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)
Comment:
TK2: PP4:Strong, PM1, PM2, PM3, PS3:Supporting
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
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.
Comment:
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.
Comment:
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).
Comment:
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.
Comment:
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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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 α4 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.
Comment:
This sequence change replaces threonine with methionine at codon 108 of the TK2 protein (p.Thr108Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs137854431, ExAC 0.009%). This variant has been reported in several families and unrelated individuals affected with mtDNA depletion syndrome, both as homozygous or in combination with other heterozygous TK2 variants (PMID: 12391347, 12873860, 15639197, 16908738, 22345218, 23303857, 26925861). It is also known as T77M in the literature. ClinVar contains an entry for this variant (Variation ID: 12710). An experimental study has shown that this missense change results in a dramatic reduction in TK2 activity compared to wild-type protein in vitro (PMID: 15639197). In addition, TK2 activity is markedly reduced in cells from affected individuals with this variant, and there is a noted depletion of mtDNA (PMID: 12391347, 12873860, 19265691, 24484525, 28812460). For these reasons, this variant has been classified as Pathogenic.
Comment:
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)
Comment:
TK2: PP4:Strong, PM1, PM2, PM3, PS3:Supporting
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
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.
Comment:
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.
Comment:
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).
Comment:
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.
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile. | Poli MC | European journal of human genetics : EJHG | 2024 | PMID: 38177409 |
| TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form. | Adam MP | - | 2018 | PMID: 23230576 |
| Myopathic mtDNA Depletion Syndrome Due to Mutation in TK2 Gene. | Martín-Hernández E | Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society | 2017 | PMID: 28812460 |
| Severe TK2 enzyme activity deficiency in patients with mild forms of myopathy. | Cámara Y | Neurology | 2015 | PMID: 25948719 |
| Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies. | Kalko SG | BMC genomics | 2014 | PMID: 24484525 |
| Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene. | Chanprasert S | Molecular genetics and metabolism | 2013 | PMID: 23932787 |
| TK2 mutation presenting as indolent myopathy. | Paradas C | Neurology | 2013 | PMID: 23303857 |
| Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum. | Béhin A | Neurology | 2012 | PMID: 22345218 |
| Altered gene transcription profiles in fibroblasts harboring either TK2 or DGUOK mutations indicate compensatory mechanisms. | Villarroya J | Experimental cell research | 2009 | PMID: 19265691 |
| Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene. | Oskoui M | Archives of neurology | 2006 | PMID: 16908738 |
| Molecular insight into mitochondrial DNA depletion syndrome in two patients with novel mutations in the deoxyguanosine kinase and thymidine kinase 2 genes. | Wang L | Molecular genetics and metabolism | 2005 | PMID: 15639197 |
| Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene. | Mancuso M | Archives of neurology | 2003 | PMID: 12873860 |
| Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA. | Mancuso M | Neurology | 2002 | PMID: 12391347 |
| Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA. | Tritschler HJ | Neurology | 1992 | PMID: 1734306 |
| - | - | - | - | PMID: 26925861 |
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Text-mined citations for rs137854431 ...
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Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.