NM_004614.5(TK2):c.323C>T (p.Thr108Met) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000199738.20

Allele description [Variation Report for NM_004614.5(TK2):c.323C>T (p.Thr108Met)]

NM_004614.5(TK2):c.323C>T (p.Thr108Met)

Gene:

TK2:thymidine kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q21

Genomic location:

Preferred name:

NM_004614.5(TK2):c.323C>T (p.Thr108Met)

Other names:

p.T108M:ACG>ATG

HGVS:

NC_000016.10:g.66531432G>A
NG_016862.1:g.23981C>T
NM_001172643.1:c.230C>T
NM_001172644.2:c.248C>T
NM_001172645.2:c.269C>T
NM_001271934.2:c.176C>T
NM_001271935.1:c.230C>T
NM_001272050.2:c.32C>T
NM_004614.5:c.323C>TMANE SELECT
NP_001166114.1:p.Thr77Met
NP_001166115.1:p.Thr83Met
NP_001166116.1:p.Thr90Met
NP_001258863.1:p.Thr59Met
NP_001258864.1:p.Thr77Met
NP_001258979.1:p.Thr11Met
NP_004605.4:p.Thr108Met
NC_000016.9:g.66565335G>A
NM_001271934.2:c.176C>T
NM_004614.4:c.323C>T
NR_073520.2:n.1312C>T
O00142:p.Thr108Met

Protein change:

T108M; THR108MET

Links:

UniProtKB: O00142#VAR_019420; OMIM: 188250.0003; dbSNP: rs137854431

NCBI 1000 Genomes Browser:

rs137854431

Molecular consequence:

NM_001172643.1:c.230C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001172644.2:c.248C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001172645.2:c.269C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001271934.2:c.176C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001271935.1:c.230C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001272050.2:c.32C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004614.5:c.323C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_073520.2:n.1312C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000252384	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 1, 2024)	germline	clinical testing	Citation Link,
SCV001414868	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 18, 2019)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 23303857, 12391347, 12873860, 24484525, 19265691, 15639197, 22345218, 28812460, 26925861, 16908738, 28492532
SCV004010494	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Sep 1, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000252384

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 1, 2024)

germline

clinical testing

Citation Link,

SCV001414868

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 18, 2019)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV004010494

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Sep 1, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

TK2 mutation presenting as indolent myopathy.

Paradas C, Gutiérrez Ríos P, Rivas E, Carbonell P, Hirano M, DiMauro S.

Neurology. 2013 Jan 29;80(5):504-6. doi: 10.1212/WNL.0b013e31827f0ff7. Epub 2013 Jan 9.

PubMed [citation]

PMID:: 23303857
PMCID:: PMC3590052

Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.

Mancuso M, Salviati L, Sacconi S, Otaegui D, Camaño P, Marina A, Bacman S, Moraes CT, Carlo JR, Garcia M, Garcia-Alvarez M, Monzon L, Naini AB, Hirano M, Bonilla E, Taratuto AL, DiMauro S, Vu TH.

Neurology. 2002 Oct 22;59(8):1197-202.

PubMed [citation]

PMID:: 12391347

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000252384.16

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001414868.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV004010494.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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