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NM_000284.4(PDHA1):c.839T>G (p.Ile280Ser) AND Pyruvate dehydrogenase complex deficiency

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Apr 2, 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:
RCV001526402.1

Allele description [Variation Report for NM_000284.4(PDHA1):c.839T>G (p.Ile280Ser)]

NM_000284.4(PDHA1):c.839T>G (p.Ile280Ser)

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.839T>G (p.Ile280Ser)
HGVS:
  • NC_000023.11:g.19357659T>G
  • NG_016781.1:g.18767T>G
  • NM_000284.4:c.839T>GMANE SELECT
  • NM_001173454.2:c.953T>G
  • NM_001173455.2:c.860T>G
  • NM_001173456.2:c.746T>G
  • NP_000275.1:p.Ile280Ser
  • NP_001166925.1:p.Ile318Ser
  • NP_001166926.1:p.Ile287Ser
  • NP_001166927.1:p.Ile249Ser
  • NC_000023.10:g.19375777T>G
  • NM_000284.3:c.839T>G
  • NM_000284.4(PDHA1):c.839T>GMANE SELECT
  • p.Ile280Ser
  • NC_000023.11:g.19357659T>G
Protein change:
I249S
Links:
dbSNP: rs1602229682
NCBI 1000 Genomes Browser:
rs1602229682
Molecular consequence:
  • NM_000284.4:c.839T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173454.2:c.953T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173455.2:c.860T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173456.2:c.746T>G - 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
SCV001736735ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen Mito Disease ACMG Specifications v1)		Uncertain significance
(Apr 2, 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, SCV001736735.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.839T>G (p.I280S) variant in the PDHA1 gene is a missense variant that has not been reported in population databases (PM2). One patient with an episodic gait disorder, speech delay, cognitive delay, elevated serum and CSF lactate and brain MRI findings consistent with Leigh syndrome has been reported in the literature with this variant (PMID: 20691944). This variant was also seen in his reportedly unaffected mother and two uncles with dystonia, which was insufficient to meet criteria of 4 or more segregations for PP1 per ClinGen SVI. Serum pyruvate levels were normal for this patient and no other biochemical studies were performed. In silico meta-predictors indicate a deleterious effect (PP3). In summary, this variant meets criteria to be classified as a variant of uncertain significance for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PM2, PP3). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 2/16/2021.

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

Last Updated: Sep 29, 2024