NM_003477.3(PDHX):c.742C>T (p.Gln248Ter) AND Pyruvate dehydrogenase E3-binding protein deficiency

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 23, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000002199.6

Allele description [Variation Report for NM_003477.3(PDHX):c.742C>T (p.Gln248Ter)]

NM_003477.3(PDHX):c.742C>T (p.Gln248Ter)

Gene:

PDHX:pyruvate dehydrogenase complex component X [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p13

Genomic location:

Preferred name:

NM_003477.3(PDHX):c.742C>T (p.Gln248Ter)

HGVS:

NC_000011.10:g.34966740C>T
NG_013368.1:g.55611C>T
NM_001135024.2:c.562C>T
NM_001166158.2:c.343-17830C>T
NM_003477.3:c.742C>TMANE SELECT
NP_001128496.2:p.Gln188Ter
NP_003468.2:p.Gln248Ter
NC_000011.9:g.34988287C>T

Protein change:

Q188*; GLN248TER

Links:

OMIM: 608769.0008; dbSNP: rs113309941

NCBI 1000 Genomes Browser:

rs113309941

Molecular consequence:

NM_001166158.2:c.343-17830C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001135024.2:c.562C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003477.3:c.742C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Pyruvate dehydrogenase E3-binding protein deficiency (PDHXD)
Synonyms:: LACTIC ACIDEMIA DUE TO DEFECT IN LIPOYL-CONTAINING COMPONENT X OF THE PYRUVATE DEHYDROGENASE COMPLEX; PYRUVATE HYDROGENASE E3-BINDING PROTEIN DEFICIENCY; E3-Binding Protein (Component X) Deficiency
Identifiers:: MONDO: MONDO:0009503; MedGen: C1855553; OMIM: 245349

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022357	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2007)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004046877	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004244362	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 23, 2024)	unknown	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

SCV000022357

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 2007)

germline

literature only

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

SCV004046877

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 23, 2023)

germline

clinical testing

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

SCV004244362

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 23, 2024)

unknown

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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A large genomic deletion in the PDHX gene caused by the retrotranspositional insertion of a full-length LINE-1 element.

Miné M, Chen JM, Brivet M, Desguerre I, Marchant D, de Lonlay P, Bernard A, Férec C, Abitbol M, Ricquier D, Marsac C.

Hum Mutat. 2007 Feb;28(2):137-42.

PubMed [citation]

PMID:: 17152059

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000022357.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

For discussion of the gln248-to-ter (Q248X) mutation in the PDHX gene that was found in compound heterozygous state in a patient with pyruvate dehydrogenase E3-binding protein deficiency (PDHXD; 245349) by Mine et al. (2007), see 608769.0007.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, SCV004046877.1

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

Description

This homozygous termination (stop-gain) [PVS1] variant is identified in a 7 year male with neonatal seizures, polydactyly and later developed severe ID with microcephaly. Metabolic acidosis and increased lactate. MRI brain: periventricular leukomalacia. This nucleotide change is absent in gnomAD database [PM2]. Insilico prediction [MutationTaster] predicts a deleterious nature of this variant. A clinvar entry for this variant is available [Variation ID: 2881] with an interpretation of “Pathogenic” [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic"

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004244362.1

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

Description

Criteria applied: PVS1,PM3,PM2_SUP

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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