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NM_000284.4(PDHA1):c.506C>T (p.Ala169Val) AND Pyruvate dehydrogenase complex deficiency

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 6, 2021
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV001526400.2

Allele description [Variation Report for NM_000284.4(PDHA1):c.506C>T (p.Ala169Val)]

NM_000284.4(PDHA1):c.506C>T (p.Ala169Val)

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.506C>T (p.Ala169Val)
Other names:
p.A169V:GCG>GTG
HGVS:
  • NC_000023.11:g.19353169C>T
  • NG_016781.1:g.14277C>T
  • NM_000284.4:c.506C>TMANE SELECT
  • NM_001173454.2:c.620C>T
  • NM_001173455.2:c.527C>T
  • NM_001173456.2:c.506C>T
  • NP_000275.1:p.Ala169Val
  • NP_001166925.1:p.Ala207Val
  • NP_001166926.1:p.Ala176Val
  • NP_001166927.1:p.Ala169Val
  • NP_001166927.1:p.Ala169Val
  • NC_000023.10:g.19371287C>T
  • NC_000023.10:g.19371287C>T
  • NM_000284.3:c.506C>T
  • NM_000284.4(PDHA1):c.506C>TMANE SELECT
  • NM_001173456.1:c.506C>T
  • p.Ala169Val
Protein change:
A169V
Links:
dbSNP: rs863224150
NCBI 1000 Genomes Browser:
rs863224150
Molecular consequence:
  • NM_000284.4:c.506C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173454.2:c.620C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173455.2:c.527C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173456.2:c.506C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Pyruvate dehydrogenase complex deficiency (PDHC)
Synonyms:
PDH DEFICIENCY; Pyruvate Dehydrogenase Complex Deficiency Disease; Pyruvate decarboxylase deficiency; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0019169; MedGen: C0034345; Orphanet: 765; Orphanet: 79243; OMIM: PS312170

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001736732ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen Mito Disease ACMG Specifications v1)		Pathogenic
(May 6, 2021) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen, SCV001736732.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.506C>T variant in the PDHA1 gene is a missense variant occurring in a hotspot domain (aa position A169, located in α β heterodimer interface (PM1). This variant is absent from population databases (PM2). This variant has been reported in three individuals in the literature with presentations consistent with PDHA1-related disease. These three cases include two assumed de novo cases (PMID: 20002461 and PMID: 21914562), and one maternity confirmed de novo case via exome sequencing in PMID: 31683770 (PS2). PMID: 20002461 Western Blot studies showed reduced E1a, and Imbard et al 2011 PDC studies indicate activity <3rd percentile in fibroblasts (PP4). In silico predictors suggest a deleterious effect (REVEL score – 0.946; PP3). In summary, this variant meets criteria to be classified as a pathogenic of PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PM1, PM2, PS2, PP3, PP4). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/6/2021.

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

Last Updated: Sep 29, 2024