VCV002839755.1 - ClinVar

NM_004614.5(TK2):c.743_744del (p.Leu247_Phe248insTer)

Germline

Classification

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.

(1)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004614.5(TK2):c.743_744del (p.Leu247_Phe248insTer)

Variation ID: 2839755 Accession: VCV002839755.1

Type and length

Deletion, 2 bp

Location

Cytogenetic: 16q21 16: 66512022-66512023 (GRCh38) [ NCBI UCSC ] 16: 66545925-66545926 (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	Feb 20, 2024	Feb 20, 2024	Feb 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004614.5:c.743_744del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004605.4:p.Leu247_Phe248insTer	nonsense
NM_001172643.1:c.650_651del	NP_001166114.1:p.Leu216_Phe217insTer	nonsense
NM_001172644.2:c.668_669del	NP_001166115.1:p.Leu222_Phe223insTer	nonsense
NM_001172645.2:c.689_690del	NP_001166116.1:p.Leu229_Phe230insTer	nonsense
NM_001271934.2:c.596_597del	NP_001258863.1:p.Leu198_Phe199insTer	nonsense
NM_001271935.1:c.40_41del		3 prime UTR
NM_001272050.2:c.452_453del	NP_001258979.1:p.Leu150_Phe151insTer	nonsense
NR_073520.2:n.1732_1733del		non-coding transcript variant
NC_000016.10:g.66512023_66512024del
NC_000016.9:g.66545926_66545927del
NG_016862.1:g.43390_43391del
NG_134023.1:g.846_847del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000016.10:66512021:AAA:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

VarSome

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
Gene	OMIM	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	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.
not provided	Pathogenic (1)	criteria provided, single submitter	Feb 22, 2023	RCV003716006.2

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 (Feb 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004504919.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 12655576 Comment: This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe248) in the TK2 gene. … (more) This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe248) in the TK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the TK2 protein. This variant has not been reported in the literature in individuals affected with TK2-related conditions. This variant disrupts a region of the TK2 protein in which other variant(s) (p.R254*) have been determined to be pathogenic (PMID: 12655576). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe248*) in the TK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the TK2 protein. This variant has not been reported in the literature in individuals affected with TK2-related conditions. This variant disrupts a region of the TK2 protein in which other variant(s) (p.R254*) have been determined to be pathogenic (PMID: 12655576). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutation analysis in 16 patients with mtDNA depletion.	Carrozzo R	Human mutation	2003	PMID: 12655576

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_004614.5(TK2):c.743_744del (p.Leu247_Phe248insTer)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...