NM_000365.6(TPI1):c.315G>C (p.Glu105Asp) AND Triosephosphate isomerase deficiency

Clinical significance:Pathogenic (Last evaluated: Dec 17, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000013284.30

Allele description [Variation Report for NM_000365.6(TPI1):c.315G>C (p.Glu105Asp)]

NM_000365.6(TPI1):c.315G>C (p.Glu105Asp)

Gene:
TPI1:triosephosphate isomerase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12p13.31
Genomic location:
Preferred name:
NM_000365.6(TPI1):c.315G>C (p.Glu105Asp)
Other names:
E104D
HGVS:
  • NC_000012.12:g.6869174G>C
  • NG_011948.1:g.6755G>C
  • NG_013308.1:g.9184C>G
  • NM_000365.6:c.315G>CMANE SELECT
  • NM_001159287.1:c.426G>C
  • NM_001258026.2:c.69G>C
  • NP_000356.1:p.Glu105Asp
  • NP_000356.1:p.Glu105Asp
  • NP_001152759.1:p.Glu142Asp
  • NP_001244955.1:p.Glu23Asp
  • LRG_1126t1:c.315G>C
  • LRG_1126:g.6755G>C
  • LRG_1126p1:p.Glu105Asp
  • NC_000012.11:g.6978338G>C
  • NM_000365.5:c.315G>C
  • P60174:p.Glu142Asp
Protein change:
E105D; GLU104ASP
Links:
UniProtKB: P60174#VAR_007536; OMIM: 190450.0001; dbSNP: rs121964845
NCBI 1000 Genomes Browser:
rs121964845
Molecular consequence:
  • NM_000365.6:c.315G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001159287.1:c.426G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258026.2:c.69G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Triosephosphate isomerase deficiency (TPID)
Identifiers:
MONDO: MONDO:0014221; MedGen: C1860808; Orphanet: 868; OMIM: 615512

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000033531OMIMno assertion criteria providedPathogenic
(Jan 1, 1997)
germlineliterature only

PubMed (5)
[See all records that cite these PMIDs]

Rodriguez-Almazan, C., Arreola, R., Rodriguez-Larrea, D., Aguirre-Lopez, B., de Gomez-Puyou, M. T., Perez-Montfort, R., Costas, M., Gomez-Puyou, A., Torres-Larios, A. Structural basis of human triosephosphate isomerase deficiency: mutation E104D is related to alterations of a conserved water network at the dimer interface. J. Biol. Chem. 283: 23254-23263, 2008.,

SCV000914600Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Pathogenic
(Dec 17, 2018)
germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link,

SCV000967685Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Dec 17, 2018)
germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedliterature only, clinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Human triosephosphate isomerase deficiency resulting from mutation of Phe-240.

Chang ML, Artymiuk PJ, Wu X, Hollán S, Lammi A, Maquat LE.

Am J Hum Genet. 1993 Jun;52(6):1260-9.

PubMed [citation]
PMID:
8503454
PMCID:
PMC1682273

Child Neurology: Triosephosphate isomerase deficiency.

Harris C, Nelson B, Farber D, Bickel S, Huxol H, Asamoah A, Morton R.

Neurology. 2020 Dec 15;95(24):e3448-e3451. doi: 10.1212/WNL.0000000000010745. Epub 2020 Sep 1. No abstract available.

PubMed [citation]
PMID:
32873690
See all PubMed Citations (18)

Details of each submission

From OMIM, SCV000033531.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (5)

Description

In 2 unrelated patients with TPI deficiency (TPID; 615512), Daar et al. (1986) identified a homozygous G-to-C transversion in the TPI1 gene, resulting in a glu104-to-asp (E104D) substitution at a highly conserved residue. The E104D substitution resulted in a thermolabile enzyme. The same homozygous mutation was identified by Chang et al. (1993) in affected members of 2 Australian families with the disorder.

Pekrun et al. (1995) found a homozygous E104D mutation in a 2-year-old girl, born of consanguineous Turkish parents, with severe TPI deficiency. TPI activity in red cells was reduced to about 20% of normal. Heat stability of the enzyme was strongly reduced; concentration of the physiologic substrate, DHAP, was increased 20-fold due to the metabolic block.

Arya et al. (1997) found that among 7 unrelated northern European kindreds with clinical TPI deficiency, the E104D mutation accounted for 11 (79%) of 14 mutant alleles. In 3 families, molecular analysis revealed compound heterozygosity for the common E104D mutation and novel missense mutations (190450.0004 and 190450.0005). Haplotype analysis indicated a founder effect.

Rodriguez-Almazan et al. (2008) determined that the E104D mutation results in instability of the TPI dimer and causes dissociation of the enzyme into inactive monomers. The substitution does not alter the catalytic residues, but it disrupts a conserved water network that spans the dimer interface and is essential for maintaining TPI dimer stability.

Harris et al. (2020) identified homozygosity for the E104D mutation in the TPI1 gene in a 20-year-old woman with TPID. She was the oldest reported patient with the disorder.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000914600.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

The TPI1 c.315G>C (p.Glu105Asp) missense variant, which is also referred to as p.Glu104Asp, is a well-known and common disease-associated variant, accounting for approximately 80% of clinical triosephosphate isomerase (TPI) deficiency. Across a selection of the available literature, the p.Glu105Asp variant was observed in 19 patients with TPI deficiency, including 13 homozygotes and six compound heterozygotes (Daar et al. 1986; Schneider et al. 1995; Arya et al. 1997; Linarello et al. 1998; Valentin et al. 2000; Yenicesu et al. 2000; Fermo et al. 2010; Sarper et al. 2013). Rodriguez-Almazan et al. (2008) demonstrated that the p.Glu105Asp variant results in instability of the TPI dimer and causes dissociation of the protein into inactive monomers, while De La Mora-De La Mora et al. (2013) showed that the p.Glu105Asp variant increases enzyme susceptibility to proteolysis. The highest allele frequency reported for this variant in the Exome Aggregation Consortium database is 0.000150 in the non-Finnish European population. Based on the collective evidence, the TPI1 p.Glu105Asp variant is classified as pathogenic for triosephosphate isomerase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000967685.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (11)

Description

The p.Glu142Asp (also known as p.Glu105Asp or p.Glu104Asp) variant in TPI1 has b een reported in at least 10 homozygous and 4 compound heterozygous individuals w ith triosephosphate isomerase deficiency (Aissa 2014, Alabdullatif 2017, Arya 19 97, Daar 1986, Nolan 2016, Pekrun 1995, Sarper 2013, Valentin 2000). It has als o been identified in 0.015% (19/129206) of European chromosomes by gnomAD (http: //gnomad.broadinstitute.org). In vitro functional studies and computational pred iction tools support an impact on protein function (Daar 1986, Ralser 2006, De L a Mora-De La Mora 2013). In summary, this variant meets criteria to be classifie d as pathogenic for autosomal recessive triosephosphate isomerase deficiency. AC MG/AMP criteria applied: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP3.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

Last Updated: Nov 27, 2021

Support Center