VCV000215275.24 - ClinVar

NM_022445.4(TPK1):c.501+4A>T

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.

(7)

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, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022445.4(TPK1):c.501+4A>T

Variation ID: 215275 Accession: VCV000215275.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q35 7: 144591419 (GRCh38) [ NCBI UCSC ] 7: 144288512 (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	Oct 26, 2024	Aug 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_022445.4:c.501+4A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001042482.2:c.354+31747A>T		intron variant
NM_001350879.1:c.501+4A>T		intron variant
NM_001350880.1:c.354+31747A>T		intron variant
NM_001350881.1:c.501+4A>T		intron variant
NM_001350882.1:c.486+4A>T		intron variant
NM_001350883.1:c.486+4A>T		intron variant
NM_001350884.2:c.486+4A>T		intron variant
NM_001350885.1:c.183+4A>T		intron variant
NM_001350886.1:c.183+4A>T		intron variant
NM_001350887.1:c.183+4A>T		intron variant
NM_001350889.1:c.183+4A>T		intron variant
NM_001350893.1:c.183+4A>T		intron variant
NM_001350894.1:c.183+4A>T		intron variant
NM_001350895.1:c.150+4A>T		intron variant
NC_000007.14:g.144591419T>A
NC_000007.13:g.144288512T>A
NG_032112.2:g.249635A>T

... more HGVS ... less HGVS

Protein change

Other names

IVS7DS, A-T, +4

Canonical SPDI

NC_000007.14:144591418:T: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.

The Genome Aggregation Database (gnomAD), exomes 0.00008

The Genome Aggregation Database (gnomAD) 0.00009

Exome Aggregation Consortium (ExAC) 0.00011

Trans-Omics for Precision Medicine (TOPMed) 0.00011

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

ClinGen: CA323751 OMIM: 606370.0002 dbSNP: rs375169579 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.
TPK1		-	-	GRCh38 GRCh38 GRCh37	299	357

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	Jun 9, 2023	RCV000199215.4
Childhood encephalopathy due to thiamine pyrophosphokinase deficiency	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Aug 13, 2024	RCV000578364.17

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 (Nov 28, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Childhood encephalopathy due to thiamine pyrophosphokinase deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680413.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Sex: female Tissue: blood
Pathogenic (Aug 12, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Childhood encephalopathy due to thiamine pyrophosphokinase deficiency Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001520668.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Jun 09, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000252398.13 First in ClinVar: Oct 11, 2015 Last updated: Aug 05, 2023	Comment: Non-canonical splice site variant demonstrated to result in loss-of-function (Mayr JA et al., 2011); This variant is associated with the following publications: (PMID: 31288420, 34426522, … (more) Non-canonical splice site variant demonstrated to result in loss-of-function (Mayr JA et al., 2011); This variant is associated with the following publications: (PMID: 31288420, 34426522, 31589614, 36175994, 31440721, 33086386, 33231275, 22152682) (less)
Pathogenic (Dec 06, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Childhood encephalopathy due to thiamine pyrophosphokinase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000960745.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 22152682‚ 17576681‚ 9536098 Comment: This sequence change falls in intron 7 of the TPK1 gene. It does not directly change the encoded amino acid sequence of the TPK1 protein. … (more) This sequence change falls in intron 7 of the TPK1 gene. It does not directly change the encoded amino acid sequence of the TPK1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs375169579, gnomAD 0.02%). This variant has been observed in individual(s) with thiamine pyrophosphokinase deficiency (PMID: 22152682). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215275). Studies have shown that this variant alters TPK1 gene expression (PMID: 22152682). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7, but is expected to preserve the integrity of the reading-frame (PMID: 22152682). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Childhood encephalopathy due to thiamine pyrophosphokinase deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002804793.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Aug 13, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Childhood encephalopathy due to thiamine pyrophosphokinase deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005381185.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Publications: PubMed (1) PubMed: 22152682 Comment: Variant summary: TPK1 c.501+4A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more) Variant summary: TPK1 c.501+4A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 8.4e-05 in 250624 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TPK1 causing Childhood Encephalopathy Due To Thiamine Pyrophosphokinase Deficiency, allowing no conclusion about variant significance. c.501+4A>T has been reported in the literature in two compound heterozygous individuals in one family affected with Childhood Encephalopathy Due To Thiamine Pyrophosphokinase Deficiency (Mayr_2011). At least one study asssessed the effect of this variant on TPK1 gene expression and the studying patient's genomic DNA shows that this variant results in skipping of exon 7 of the TPK1 gene (Mayr_-2011). These data suggests that this variant is associated with disease. These data indicate that the variant is likely associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 22152682). ClinVar contains an entry for this variant (Variation ID: 215275). Based on the evidence outlined above, the variant was classified as pathogenic. (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: SCV000044823.4 First in ClinVar: Apr 04, 2013 Last updated: Nov 11, 2023	Publications: PubMed (2) PubMed: 22152682‚ 33086386 Comment on evidence: For discussion of the splice site mutation in the TPK1 gene (501+4A-T) that was found in compound heterozygous state in 2 sisters with episodic encephalopathy … (more) For discussion of the splice site mutation in the TPK1 gene (501+4A-T) that was found in compound heterozygous state in 2 sisters with episodic encephalopathy due to thiamine metabolism dysfunction syndrome-5 (THMD5; 614458) by Mayr et al. (2011), see 606370.0001. In a patient with THMD5, Eckenweiler et al. (2021) identified compound heterozygous mutations in the TPK1 gene: c.501+4A-T, resulting in a deletion (Val119_Pro167del), and a c.479C-T transition, resulting in a ser160-to-leu (S160L; 606370.0006) substitution. The mutations were identified by next-generation sequencing of a panel of genes associated with Leigh syndrome (see 256000). Western blot analysis in patient fibroblasts demonstrated reduction in TPK1 protein compared to controls. (less)

Comment:

Non-canonical splice site variant demonstrated to result in loss-of-function (Mayr JA et al., 2011); This variant is associated with the following publications: (PMID: 31288420, 34426522, 31589614, 36175994, 31440721, 33086386, 33231275, 22152682)

Comment:

This sequence change falls in intron 7 of the TPK1 gene. It does not directly change the encoded amino acid sequence of the TPK1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs375169579, gnomAD 0.02%). This variant has been observed in individual(s) with thiamine pyrophosphokinase deficiency (PMID: 22152682). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215275). Studies have shown that this variant alters TPK1 gene expression (PMID: 22152682). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7, but is expected to preserve the integrity of the reading-frame (PMID: 22152682). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: TPK1 c.501+4A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 8.4e-05 in 250624 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TPK1 causing Childhood Encephalopathy Due To Thiamine Pyrophosphokinase Deficiency, allowing no conclusion about variant significance. c.501+4A>T has been reported in the literature in two compound heterozygous individuals in one family affected with Childhood Encephalopathy Due To Thiamine Pyrophosphokinase Deficiency (Mayr_2011). At least one study asssessed the effect of this variant on TPK1 gene expression and the studying patient's genomic DNA shows that this variant results in skipping of exon 7 of the TPK1 gene (Mayr_-2011). These data suggests that this variant is associated with disease. These data indicate that the variant is likely associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 22152682). ClinVar contains an entry for this variant (Variation ID: 215275). Based on the evidence outlined above, the variant was 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
Thiamine Treatment and Favorable Outcome in an Infant with Biallelic TPK1 Variants.	Eckenweiler M	Neuropediatrics	2021	PMID: 33086386
Thiamine pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway.	Mayr JA	American journal of human genetics	2011	PMID: 22152682
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs375169579 ...

These 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 27, 2024

ClinVar Genomic variation as it relates to human health

NM_022445.4(TPK1):c.501+4A>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs375169579 ...