NM_022445.4(TPK1):c.152G>A (p.Arg51His) AND Childhood encephalopathy due to thiamine pyrophosphokinase deficiency

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 19, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000813012.5

Allele description [Variation Report for NM_022445.4(TPK1):c.152G>A (p.Arg51His)]

NM_022445.4(TPK1):c.152G>A (p.Arg51His)

Gene:

TPK1:thiamin pyrophosphokinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q35

Genomic location:

Preferred name:

NM_022445.4(TPK1):c.152G>A (p.Arg51His)

HGVS:

NC_000007.14:g.144682942C>T
NG_032112.2:g.158112G>A
NM_001042482.2:c.152G>A
NM_001350879.1:c.152G>A
NM_001350880.1:c.152G>A
NM_001350881.1:c.152G>A
NM_001350882.1:c.16G>A
NM_001350883.1:c.16G>A
NM_001350884.2:c.16G>A
NM_001350885.1:c.-133-34063G>A
NM_001350886.1:c.-245G>A
NM_001350887.1:c.-94G>A
NM_001350889.1:c.-60-59681G>A
NM_001350893.1:c.-133-34063G>A
NM_001350894.1:c.-94G>A
NM_001350895.1:c.-322G>A
NM_022445.4:c.152G>AMANE SELECT
NP_001035947.1:p.Arg51His
NP_001337808.1:p.Arg51His
NP_001337809.1:p.Arg51His
NP_001337810.1:p.Arg51His
NP_001337811.1:p.Ala6Thr
NP_001337812.1:p.Ala6Thr
NP_001337813.1:p.Ala6Thr
NP_071890.2:p.Arg51His
NC_000007.13:g.144380035C>T
NM_022445.3:c.152G>A
NR_146934.1:n.196G>A
NR_146936.2:n.200G>A

Protein change:

A6T

Links:

dbSNP: rs202038293

NCBI 1000 Genomes Browser:

rs202038293

Molecular consequence:

NM_001350886.1:c.-245G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350887.1:c.-94G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350894.1:c.-94G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350895.1:c.-322G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350885.1:c.-133-34063G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001350889.1:c.-60-59681G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001350893.1:c.-133-34063G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001042482.2:c.152G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350879.1:c.152G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350880.1:c.152G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350881.1:c.152G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350882.1:c.16G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350883.1:c.16G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350884.2:c.16G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_022445.4:c.152G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_146934.1:n.196G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146936.2:n.200G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Childhood encephalopathy due to thiamine pyrophosphokinase deficiency
Synonyms:: ENCEPHALOPATHY, EPISODIC, DUE TO THIAMINE PYROPHOSPHOKINASE DEFICIENCY; Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type)
Identifiers:: MONDO: MONDO:0013761; MedGen: C3280866; Orphanet: 293955; OMIM: 614458

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000953345	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000953345

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 19, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000953345.5

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 51 of the TPK1 protein (p.Arg51His). This variant is present in population databases (rs202038293, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TPK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 656563). 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 not expected to disrupt TPK1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

Last Updated: Dec 24, 2023

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