The frameshift deletion p.Y148Ifs*12 in TK2 (NM_004614.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Y148Ifs*12 variant has a GnomAD frequency of 0.002387 % and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 12 residues until a stop codon is reached. The p.Y148Ifs*12 variant is a loss of function variant in the gene TK2, which is intolerant of Loss of Function variants. For these reasons, this variant has been classified as Likely Pathogenic. The observed variant was also detected in heterozygous state in the mother.
ClinVar Genomic variation as it relates to human health
NM_004614.5(TK2):c.441del (p.Tyr148fs)
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.
(7)
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/Likely pathogenic
7
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.441del (p.Tyr148fs)
Variation ID: 1323691 Accession: VCV001323691.18
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 16q21 16: 66529002 (GRCh38) [ NCBI UCSC ] 16: 66562905 (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 Nov 29, 2021 Oct 20, 2024 Feb 15, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004614.5:c.441del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004605.4:p.Tyr148fs frameshift NM_001172643.1:c.348del NP_001166114.1:p.Tyr117fs frameshift NM_001172644.2:c.366del NP_001166115.1:p.Tyr123fs frameshift NM_001172645.2:c.387del NP_001166116.1:p.Tyr130fs frameshift NM_001271934.2:c.294del NP_001258863.1:p.Tyr99fs frameshift NM_001271935.1:c.348del NP_001258864.1:p.Tyr117fs frameshift NM_001272050.2:c.150del NP_001258979.1:p.Tyr51fs frameshift NR_073520.2:n.1430del non-coding transcript variant NC_000016.10:g.66529002del NC_000016.9:g.66562905del NG_016862.1:g.26411del - Protein change
- Y117fs, Y123fs, Y130fs, Y148fs, Y51fs, Y99fs
- Other names
- -
- Canonical SPDI
- NC_000016.10:66529001:C:
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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 0.00002
- 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. |
|||
| 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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 15, 2024 | RCV001785065.17 | |
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 13, 2023 | RCV003388613.6 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 22, 2022 | RCV004554871.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Oct 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome, myopathic form
Affected status: yes
Allele origin:
biparental
|
Institute of Human Genetics, Heidelberg University
Accession: SCV004100314.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Sex: male
|
|
|
Likely 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: SCV004101503.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The frameshift deletion p.Y148Ifs*12 in TK2 (NM_004614.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The … (more)
The frameshift deletion p.Y148Ifs*12 in TK2 (NM_004614.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Y148Ifs*12 variant has a GnomAD frequency of 0.002387 % and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 12 residues until a stop codon is reached. The p.Y148Ifs*12 variant is a loss of function variant in the gene TK2, which is intolerant of Loss of Function variants. For these reasons, this variant has been classified as Likely Pathogenic. The observed variant was also detected in heterozygous state in the mother. (less)
Clinical Features:
Bradykinesia (present) , Dyspnea (present) , Muscle stiffness (present) , Joint contracture (present) , Myopathy (present)
|
|
|
Likely pathogenic
(Nov 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018975.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Dec 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004617114.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr148Ilefs*12) in the TK2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr148Ilefs*12) in the TK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TK2 are known to be pathogenic (PMID: 20421844). This variant is present in population databases (rs768548319, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1323691). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Sep 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3
Mitochondrial DNA depletion syndrome, myopathic form
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
inherited
|
New York Genome Center
Study: PrenatalSEQ
Accession: SCV005044143.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024 |
Comment:
The homozygous c.441del, p.(Tyr148IlefsTer12) variant identified in the TK2 gene is the deletion of a single nucleotide within exon 6/10 (amino acid 148/266) and is … (more)
The homozygous c.441del, p.(Tyr148IlefsTer12) variant identified in the TK2 gene is the deletion of a single nucleotide within exon 6/10 (amino acid 148/266) and is predicted to lead to a frameshift and a premature termination of the protein approximately 12 amino acids downstream. This variant is identified with low frequency in population databases (gnomADv2.1.1, gnomADv3.1.2, TOPMed Freeze 8, All of Us), with highest allele frequency of 2.45e-5 (gnomADv2.1.1, 0 homozygotes), suggesting it is not a common benign variant in the populations represented in those databases. This variant has been reported by a clinical lab as Pathogenic in ClinVar (VarID:1323691), however the assertion criteria used for that classification is not available for our review. Other nonsense and frameshift variants downstream of the one identified here have also been reported as Pathogenic or Likely Pathogenic in ClinVar (VarIDs:1327192, 280624, 1414250). While the p.(Tyr148IlefsTer12) variant has not been previously reported in affected individuals in the literature, other nonsense and frameshift variants downstream have been reported in individuals with variable clinical presentations [for review, PMID:29735374, 29602790]. Given its deleterious nature and absence in population databases, the homozygous c.441del, p.(Tyr148IlefsTer12) variant identified in the TK2 gene is reported here as Likely Pathogenic. (less)
Clinical Features:
Microcephaly (present) , Lissencephaly (present) , Cerebellar hypoplasia (present)
Age: 30-39 weeks gestation
Secondary finding: no
|
|
|
Pathogenic
(Feb 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005079856.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge (less)
|
|
|
Likely pathogenic
(Jan 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004139930.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
TK2: PVS1:Strong, PM2
Number of individuals with the variant: 1
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Tyr148Ilefs*12) in the TK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TK2 are known to be pathogenic (PMID: 20421844). This variant is present in population databases (rs768548319, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1323691). For these reasons, this variant has been classified as Pathogenic.
Comment:
The homozygous c.441del, p.(Tyr148IlefsTer12) variant identified in the TK2 gene is the deletion of a single nucleotide within exon 6/10 (amino acid 148/266) and is predicted to lead to a frameshift and a premature termination of the protein approximately 12 amino acids downstream. This variant is identified with low frequency in population databases (gnomADv2.1.1, gnomADv3.1.2, TOPMed Freeze 8, All of Us), with highest allele frequency of 2.45e-5 (gnomADv2.1.1, 0 homozygotes), suggesting it is not a common benign variant in the populations represented in those databases. This variant has been reported by a clinical lab as Pathogenic in ClinVar (VarID:1323691), however the assertion criteria used for that classification is not available for our review. Other nonsense and frameshift variants downstream of the one identified here have also been reported as Pathogenic or Likely Pathogenic in ClinVar (VarIDs:1327192, 280624, 1414250). While the p.(Tyr148IlefsTer12) variant has not been previously reported in affected individuals in the literature, other nonsense and frameshift variants downstream have been reported in individuals with variable clinical presentations [for review, PMID:29735374, 29602790]. Given its deleterious nature and absence in population databases, the homozygous c.441del, p.(Tyr148IlefsTer12) variant identified in the TK2 gene is reported here as Likely Pathogenic.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Comment:
TK2: PVS1:Strong, PM2
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 frameshift deletion p.Y148Ifs*12 in TK2 (NM_004614.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Y148Ifs*12 variant has a GnomAD frequency of 0.002387 % and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. The frame shifted sequence continues 12 residues until a stop codon is reached. The p.Y148Ifs*12 variant is a loss of function variant in the gene TK2, which is intolerant of Loss of Function variants. For these reasons, this variant has been classified as Likely Pathogenic. The observed variant was also detected in heterozygous state in the mother.
Comment:
This sequence change creates a premature translational stop signal (p.Tyr148Ilefs*12) in the TK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TK2 are known to be pathogenic (PMID: 20421844). This variant is present in population databases (rs768548319, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1323691). For these reasons, this variant has been classified as Pathogenic.
Comment:
The homozygous c.441del, p.(Tyr148IlefsTer12) variant identified in the TK2 gene is the deletion of a single nucleotide within exon 6/10 (amino acid 148/266) and is predicted to lead to a frameshift and a premature termination of the protein approximately 12 amino acids downstream. This variant is identified with low frequency in population databases (gnomADv2.1.1, gnomADv3.1.2, TOPMed Freeze 8, All of Us), with highest allele frequency of 2.45e-5 (gnomADv2.1.1, 0 homozygotes), suggesting it is not a common benign variant in the populations represented in those databases. This variant has been reported by a clinical lab as Pathogenic in ClinVar (VarID:1323691), however the assertion criteria used for that classification is not available for our review. Other nonsense and frameshift variants downstream of the one identified here have also been reported as Pathogenic or Likely Pathogenic in ClinVar (VarIDs:1327192, 280624, 1414250). While the p.(Tyr148IlefsTer12) variant has not been previously reported in affected individuals in the literature, other nonsense and frameshift variants downstream have been reported in individuals with variable clinical presentations [for review, PMID:29735374, 29602790]. Given its deleterious nature and absence in population databases, the homozygous c.441del, p.(Tyr148IlefsTer12) variant identified in the TK2 gene is reported here as Likely Pathogenic.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Comment:
TK2: PVS1:Strong, PM2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Hearing loss in a patient with the myopathic form of mitochondrial DNA depletion syndrome and a novel mutation in the TK2 gene. | Martí R | Pediatric research | 2010 | PMID: 20421844 |
Text-mined citations for rs768548319 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
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.