ClinVar Genomic variation as it relates to human health
NM_004614.5(TK2):c.416C>T (p.Ala139Val)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004614.5(TK2):c.416C>T (p.Ala139Val)
Variation ID: 38990 Accession: VCV000038990.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16q21 16: 66529027 (GRCh38) [ NCBI UCSC ] 16: 66562930 (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 Mar 16, 2024 Dec 5, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_004614.5:c.416C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004605.4:p.Ala139Val missense NM_001172643.1:c.323C>T NP_001166114.1:p.Ala108Val missense NM_001172644.2:c.341C>T NP_001166115.1:p.Ala114Val missense NM_001172645.2:c.362C>T NP_001166116.1:p.Ala121Val missense NM_001271934.2:c.269C>T NP_001258863.1:p.Ala90Val missense NM_001271935.1:c.323C>T NP_001258864.1:p.Ala108Val missense NM_001272050.2:c.125C>T NP_001258979.1:p.Ala42Val missense NR_073520.2:n.1405C>T non-coding transcript variant NC_000016.10:g.66529027G>A NC_000016.9:g.66562930G>A NG_016862.1:g.26386C>T O00142:p.Ala139Val - Protein change
- A139V, A90V, A108V, A114V, A121V, A42V
- Other names
- p.A139V:GCA>GTA
- Canonical SPDI
- NC_000016.10:66529026:G:A
-
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.
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00008
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00008
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. |
|||
TK2 | - | - |
GRCh38 GRCh37 |
451 | 552 |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 5, 2023 | RCV000197645.17 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 14, 2022 | RCV000615451.12 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000762977.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 28, 2023 | RCV003904881.1 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome, myopathic form
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893421.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(Jul 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004238379.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Oct 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
TK2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004723604.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The TK2 c.416C>T variant is predicted to result in the amino acid substitution p.Ala139Val. This variant has been reported in individuals with autosomal recessive mitochondrial … (more)
The TK2 c.416C>T variant is predicted to result in the amino acid substitution p.Ala139Val. This variant has been reported in individuals with autosomal recessive mitochondrial DNA depletion syndrome (referred to as c.542C>T, p.Ala181Val, Fig 3b, Galbiati et al. 2006. PubMed ID: 16504786; Knierim et al. 2014. PubMed ID: 25446393; Mazurova et al. 2016. PubMed ID: 27839525; Figure 2, Garone et al. 2018. PubMed ID: 29602790; Table S3, Ganapathy et al. 2019. PubMed ID: 31069529; Papadimas et al. 2020. PubMed ID: 32904881). This variant is reported in 0.0046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-66562930-G-A). This variant is interpreted as pathogenic. (less)
|
|
Likely pathogenic
(Sep 21, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000713499.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Ala139Val (NM_004614.4 c.416C>T) (also referred to as p.Ala181Val in the l iterature) variant in TK2 has been reported in one compound heterozygous and one … (more)
The p.Ala139Val (NM_004614.4 c.416C>T) (also referred to as p.Ala181Val in the l iterature) variant in TK2 has been reported in one compound heterozygous and one homozygous patients with mitochondrial DNA depletion syndrome and segregated in two affected siblings from two families (Galbiati 2006 and Knierim 2015). This variant has also been reported in ClinVar (Variation ID#5782). It has been ident ified in 5/126,712 of European chromosomes by the Genome Aggregation Database (g nomAD, http://gnomad.broadinstitute.org; dbSNP rs281865494). Although this varia nt has been seen in the general population, its frequency is low enough to be co nsistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that the p.Ala139Val variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clin ical significance, the p.Ala139Val variant is likely pathogenic for TK2-related mitochondrial DNA depletion syndrome in an autosomal recessive manner based on i ts occurrence in individuals with this disease and low frequency in the general population. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Dec 14, 2022)
|
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: SCV002819530.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: TK2 c.416C>T (p.Ala139Val) results in a non-conservative amino acid change located in the Deoxynucleoside kinase domain (IPR031314) of the encoded protein sequence. Five … (more)
Variant summary: TK2 c.416C>T (p.Ala139Val) 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 2.8e-05 in 251356 control chromosomes (gnomAD). c.416C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Mitochondrial DNA Depletion Syndrome - TK2 Related, and segregated with disease within families (e.g. Galbiati_2006, Knierim_2015, Wahbi_2015, Mazurova_2017). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Feb 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000252380.12
First in ClinVar: Oct 11, 2015 Last updated: Mar 04, 2023 |
Comment:
Quantitative PCR analysis demonstrates marked depletion of mtDNA copy numbers in skeletal muscle from affected individuals (Knierim et al., 2015).; Not observed at a significant … (more)
Quantitative PCR analysis demonstrates marked depletion of mtDNA copy numbers in skeletal muscle from affected individuals (Knierim et al., 2015).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30609409, 29602790, 25446393, 27839525, 16504786) (less)
|
|
Pathogenic
(Dec 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002246002.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 139 of the TK2 protein (p.Ala139Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 139 of the TK2 protein (p.Ala139Val). This variant is present in population databases (rs281865494, gnomAD 0.004%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 16504786, 25446393). It has also been observed to segregate with disease in related individuals. This variant is also known as A181V. ClinVar contains an entry for this variant (Variation ID: 38990). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002034973.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035123.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Thymidine kinase 2 and alanyl-tRNA synthetase 2 deficiencies cause lethal mitochondrial cardiomyopathy: case reports and review of the literature. | Mazurova S | Cardiology in the young | 2017 | PMID: 27839525 |
Long-term cardiac prognosis and risk stratification in 260 adults presenting with mitochondrial diseases. | Wahbi K | European heart journal | 2015 | PMID: 26224072 |
Clinical application of whole exome sequencing reveals a novel compound heterozygous TK2-mutation in two brothers with rapidly progressive combined muscle-brain atrophy, axonal neuropathy, and status epilepticus. | Knierim E | Mitochondrion | 2015 | PMID: 25446393 |
New mutations in TK2 gene associated with mitochondrial DNA depletion. | Galbiati S | Pediatric neurology | 2006 | PMID: 16504786 |
Text-mined citations for rs281865494 ...
HelpRecord last updated Apr 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.