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NM_000284.4(PDHA1):c.999A>C (p.Glu333Asp) AND Pyruvate dehydrogenase complex deficiency

Germline classification:
Benign (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:
RCV001526401.8

Allele description [Variation Report for NM_000284.4(PDHA1):c.999A>C (p.Glu333Asp)]

NM_000284.4(PDHA1):c.999A>C (p.Glu333Asp)

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.999A>C (p.Glu333Asp)
HGVS:
  • NC_000023.11:g.19359015A>C
  • NG_016781.1:g.20123A>C
  • NG_021184.1:g.161247T>G
  • NM_000284.4:c.999A>CMANE SELECT
  • NM_001173454.1:c.1113A>C
  • NM_001173454.2:c.1113A>C
  • NM_001173455.2:c.1020A>C
  • NM_001173456.2:c.906A>C
  • NP_000275.1:p.Glu333Asp
  • NP_001166925.1:p.Glu371Asp
  • NP_001166926.1:p.Glu340Asp
  • NP_001166927.1:p.Glu302Asp
  • NC_000023.10:g.19377133A>C
  • NM_000284.3:c.999A>C
  • NM_000284.4(PDHA1):c.999A>CMANE SELECT
  • p.Glu333Asp
Protein change:
E302D
Links:
dbSNP: rs2228067
NCBI 1000 Genomes Browser:
rs2228067
Molecular consequence:
  • NM_000284.4:c.999A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173454.2:c.1113A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173455.2:c.1020A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173456.2:c.906A>C - 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
SCV001736733ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen Mito Disease ACMG Specifications v1)		Benign
(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, SCV001736733.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The allele frequency of the c.999A>C variant in the PDHA1 gene is 0.044% in gnomAD, including 25 hemizygotes. This allele frequency, and the frequency with which it is seen in hemizygotes in the general population are high enough to be classified as benign based on thresholds defined by the ClinGen PDHA1 Variant Curation Expert Panel (>0.0092%- BS1; gnomAD >16 hemizygotes- BS2). In silico predictors provide a conflicting score (REVEL score 0.509). In summary, this variant meets criteria to be classified as benign for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (BS1, BS2). 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: Jul 29, 2024