ClinVar Genomic variation as it relates to human health
NM_022445.4(TPK1):c.656A>G (p.Asn219Ser)
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.
Pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_022445.4(TPK1):c.656A>G (p.Asn219Ser)
Variation ID: 30572 Accession: VCV000030572.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q35 7: 144453621 (GRCh38) [ NCBI UCSC ] 7: 144150714 (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 Jun 28, 2015 May 1, 2024 May 16, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_022445.4:c.656A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071890.2:p.Asn219Ser missense NM_001042482.2:c.509A>G NP_001035947.1:p.Asn170Ser missense NM_001350879.1:c.656A>G NP_001337808.1:p.Asn219Ser missense NM_001350880.1:c.509A>G NP_001337809.1:p.Asn170Ser missense NM_001350881.1:c.*36A>G 3 prime UTR NM_001350882.1:c.641A>G NP_001337811.1:p.Asn214Ser missense NM_001350883.1:c.641A>G NP_001337812.1:p.Asn214Ser missense NM_001350884.2:c.641A>G NP_001337813.1:p.Asn214Ser missense NM_001350885.1:c.338A>G NP_001337814.1:p.Asn113Ser missense NM_001350886.1:c.338A>G NP_001337815.1:p.Asn113Ser missense NM_001350887.1:c.338A>G NP_001337816.1:p.Asn113Ser missense NM_001350889.1:c.338A>G NP_001337818.1:p.Asn113Ser missense NM_001350893.1:c.338A>G NP_001337822.1:p.Asn113Ser missense NM_001350894.1:c.338A>G NP_001337823.1:p.Asn113Ser missense NM_001350895.1:c.305A>G NP_001337824.1:p.Asn102Ser missense NR_146934.1:n.553A>G non-coding transcript variant NR_146935.1:n.692A>G non-coding transcript variant NR_146936.2:n.1111A>G non-coding transcript variant NC_000007.14:g.144453621T>C NC_000007.13:g.144150714T>C NG_032112.2:g.387433A>G Q9H3S4:p.Asn219Ser - Protein change
- N219S, N102S, N113S, N214S, N170S
- Other names
- -
- Canonical SPDI
- NC_000007.14:144453620:T:C
-
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) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 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. |
|||
TPK1 | - | - |
GRCh38 GRCh38 GRCh37 |
294 | 352 |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
May 16, 2023 | RCV000023535.7 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jun 17, 2015 | RCV000437841.1 | |
Uncertain significance (1) |
criteria provided, single submitter
|
May 25, 2022 | RCV002513193.2 |
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
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Childhood encephalopathy due to thiamine pyrophosphokinase deficiency
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003256098.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPK1 function (PMID: 30483896). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPK1 function (PMID: 30483896). 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 expected to disrupt TPK1 protein function. ClinVar contains an entry for this variant (Variation ID: 30572). This missense change has been observed in individual(s) with thiamine metabolism dysfunction syndrome (PMID: 22152682, 28747443). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs371271054, gnomAD 0.02%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 219 of the TPK1 protein (p.Asn219Ser). (less)
|
|
Pathogenic
(Jun 17, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000517229.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The N219S missense variant in the TPK1 gene has been reported previously in association with thiaminepyrophosphokinase deficiency in a patient who was compound heterozygous for … (more)
The N219S missense variant in the TPK1 gene has been reported previously in association with thiaminepyrophosphokinase deficiency in a patient who was compound heterozygous for N219S and a frameshiftvariant (Mayr et al. 2011). N219S occurs at a position that is conserved across species, in silico analysispredicts that N219S is probably damaging to the protein structure/function, and a missense variant in anearby residue (D222H) has also been reported in the Human Gene Mutation Database in association withthiamine pyrophosphokinase deficiency (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. Therefore, we interpret N219S to be a pathogenic variant. (less)
|
|
Pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Childhood encephalopathy due to thiamine pyrophosphokinase deficiency
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369604.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM2,PM3,PP2,PP3.
|
|
Uncertain significance
(May 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003735974.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.656A>G (p.N219S) alteration is located in exon 9 (coding exon 8) of the TPK1 gene. This alteration results from a A to G substitution … (more)
The c.656A>G (p.N219S) alteration is located in exon 9 (coding exon 8) of the TPK1 gene. This alteration results from a A to G substitution at nucleotide position 656, causing the asparagine (N) at amino acid position 219 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
|
|
Pathogenic
(Dec 09, 2011)
|
no assertion criteria provided
Method: literature only
|
THIAMINE METABOLISM DYSFUNCTION SYNDROME 5 (EPISODIC ENCEPHALOPATHY TYPE)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044826.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 28, 2015 |
Comment on evidence:
For discussion of the asn219-to-ser (N219S) mutation in the TPK1 gene that was found in compound heterozygous state in a patient with thiamine metabolism dysfunction … (more)
For discussion of the asn219-to-ser (N219S) mutation in the TPK1 gene that was found in compound heterozygous state in a patient with thiamine metabolism dysfunction syndrome-5 (THMD5; 614458) by Mayr et al. (2011), see 606370.0004. (less)
|
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 |
---|---|---|---|---|
Reduced thiamine binding is a novel mechanism for TPK deficiency disorder. | Huang W | Molecular genetics and genomics : MGG | 2019 | PMID: 30483896 |
Thiamine-responsive disease due to mutation of tpk1: Importance of avoiding misdiagnosis. | Invernizzi F | Neurology | 2017 | PMID: 28747443 |
Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway. | Mayr JA | American journal of human genetics | 2011 | PMID: 22152682 |
Text-mined citations for rs371271054 ...
HelpRecord last updated May 01, 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.