NM_000284.4(PDHA1):c.863G>A (p.Arg288His) AND Pyruvate dehydrogenase E1-alpha deficiency

Clinical significance:Pathogenic (Last evaluated: Nov 1, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000011637.9

Allele description [Variation Report for NM_000284.4(PDHA1):c.863G>A (p.Arg288His)]

NM_000284.4(PDHA1):c.863G>A (p.Arg288His)

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.863G>A (p.Arg288His)
HGVS:
  • NC_000023.11:g.19357683G>A
  • NG_016781.1:g.18791G>A
  • NM_000284.4:c.863G>AMANE SELECT
  • NM_001173454.2:c.977G>A
  • NM_001173455.2:c.884G>A
  • NM_001173456.2:c.770G>A
  • NP_000275.1:p.Arg288His
  • NP_001166925.1:p.Arg326His
  • NP_001166925.1:p.Arg326His
  • NP_001166926.1:p.Arg295His
  • NP_001166927.1:p.Arg257His
  • NC_000023.10:g.19375801G>A
  • NM_001173454.1:c.977G>A
  • P08559:p.Arg288His
Protein change:
R257H; ARG288HIS
Links:
UniProtKB: P08559#VAR_021055; OMIM: 300502.0020; dbSNP: rs137853258
NCBI 1000 Genomes Browser:
rs137853258
Molecular consequence:
  • NM_000284.4:c.863G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173454.2:c.977G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173455.2:c.884G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173456.2:c.770G>A - missense variant - [Sequence Ontology: SO:0001583]

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000031869OMIMno assertion criteria providedPathogenic
(Oct 1, 1999)
germlineliterature only

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

SCV001443728Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diegocriteria provided, single submitter
Pathogenic
(Nov 1, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Cerebral palsy and pyruvate dehydrogenase deficiency: identification of two new mutations in the E1alpha gene.

Lissens W, Vreken P, Barth PG, Wijburg FA, Ruitenbeek W, Wanders RJ, Seneca S, Liebaers I, De Meirleir L.

Eur J Pediatr. 1999 Oct;158(10):853-7.

PubMed [citation]
PMID:
10486093

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, SCV000031869.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a 13-year-old girl with pyruvate dehydrogenase E1-alpha deficiency (PDHAD; 312170), Lissens et al. (1999) identified an arg288-to-his (R288H) substitution in exon 9 of the E1-alpha gene. The parents were not available for study. X-inactivation studies in fibroblast DNA showed that the patient had an almost completely skewed inactivation pattern.

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

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001443728.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant (also referred to as p.Arg288His) has been previously reported as a heterozygous change in a similarly affected female with pyruvate dehydrogenase deficiency and skewed X-inactivation within fibroblasts (PMID: 10486093). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.977G>A (p.Arg326His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function.Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.977G>A (p.Arg326His) variant is classified as Pathogenic.

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

Last Updated: Dec 4, 2021

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