NM_000284.4(PDHA1):c.1132C>T (p.Arg378Cys) AND Pyruvate dehydrogenase E1-alpha deficiency

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 27, 2022
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:: RCV000497402.14

Allele description

NM_000284.4(PDHA1):c.1132C>T (p.Arg378Cys)

Gene:

PDHA1:pyruvate dehydrogenase E1 subunit alpha 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp22.12

Genomic location:

Preferred name:

NM_000284.4(PDHA1):c.1132C>T (p.Arg378Cys)

Other names:

p.R378C:CGT>TGT; NM_000284.3(PDHA1):c.1132C>T; p.Arg378Cys

HGVS:

NC_000023.11:g.19359612C>T
NG_016781.1:g.20720C>T
NG_021184.1:g.160650G>A
NM_000284.4:c.1132C>TMANE SELECT
NM_001173454.2:c.1246C>T
NM_001173455.2:c.1153C>T
NM_001173456.2:c.1039C>T
NP_000275.1:p.Arg378Cys
NP_001166925.1:p.Arg416Cys
NP_001166926.1:p.Arg385Cys
NP_001166927.1:p.Arg347Cys
NC_000023.10:g.19377730C>T
NM_000284.3:c.1132C>T
NM_001173454.1:c.1246C>T
p.(Arg378Cys)

Protein change:

R347C

Links:

dbSNP: rs863224147

NCBI 1000 Genomes Browser:

rs863224147

Molecular consequence:

NM_000284.4:c.1132C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173454.2:c.1246C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173455.2:c.1153C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173456.2:c.1039C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Pyruvate dehydrogenase E1-alpha deficiency (PDHAD)
Synonyms:: X-linked Leigh syndrome; ATAXIA, INTERMITTENT, WITH PYRUVATE DEHYDROGENASE DEFICIENCY; ATAXIA WITH LACTIC ACIDOSIS I; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010717; MedGen: C1839413; OMIM: 312170

Recent activity

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AGENCOURT_6626349 NIH_MGC_115 Homo sapiens cDNA clone IMAGE:5752719 5', mRNA seq...
AGENCOURT_6626349 NIH_MGC_115 Homo sapiens cDNA clone IMAGE:5752719 5', mRNA sequence
gi|19371696|gnl|dbEST|11604741|gb|B 17.1|

Nucleotide
LOC130062452 [Homo sapiens]
LOC130062452 [Homo sapiens]
Gene ID:130062452

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000590879	Center of Genomic medicine, Geneva, University Hospital of Geneva	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 7, 2017)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001393905	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 27, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8962591, 20002125, 20002461, 24718837, 28639102, 28492532
SCV001429428	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 20, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002016567	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 29, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Pyruvate dehydrogenase deficiency: the relation of the E1 alpha mutation to the E1 beta subunit deficiency.

Fujii T, Garcia Alvarez MB, Sheu KF, Kranz-Eble PJ, De Vivo DC.

Pediatr Neurol. 1996 May;14(4):328-34.

PubMed [citation]

PMID:: 8962591

Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis.

Barnerias C, Saudubray JM, Touati G, De Lonlay P, Dulac O, Ponsot G, Marsac C, Brivet M, Desguerre I.

Dev Med Child Neurol. 2010 Feb;52(2):e1-9. doi: 10.1111/j.1469-8749.2009.03541.x. Epub 2009 Dec 1.

PubMed [citation]

PMID:: 20002125

See all PubMed Citations (7)

Details of each submission

From Center of Genomic medicine, Geneva, University Hospital of Geneva, SCV000590879.1

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

Description

This missense variant in the PDHA1 gene was identified in a female patient with developmental delay and neurological disorder.

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

From Invitae, SCV001393905.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDHA1 protein function. ClinVar contains an entry for this variant (Variation ID: 214936). This missense change has been observed in individual(s) with pyruvate dehydrogenase lipoic acid synthetase deficiency (PMID: 8962591, 20002125, 20002461, 24718837, 28639102). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 378 of the PDHA1 protein (p.Arg378Cys).

#	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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429428.1

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

#	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 Revvity Omics, Revvity, SCV002016567.3

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

#	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: May 19, 2024

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