NM_000284.4(PDHA1):c.692C>G (p.Thr231Arg) AND Pyruvate dehydrogenase E1-alpha deficiency

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Jul 31, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000805497.4

Allele description [Variation Report for NM_000284.4(PDHA1):c.692C>G (p.Thr231Arg)]

NM_000284.4(PDHA1):c.692C>G (p.Thr231Arg)

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.692C>G (p.Thr231Arg)
HGVS:
  • NC_000023.11:g.19355437C>G
  • NG_016781.1:g.16545C>G
  • NM_000284.4:c.692C>GMANE SELECT
  • NM_001173454.2:c.806C>G
  • NM_001173455.2:c.713C>G
  • NM_001173456.2:c.599C>G
  • NP_000275.1:p.Thr231Arg
  • NP_001166925.1:p.Thr269Arg
  • NP_001166926.1:p.Thr238Arg
  • NP_001166927.1:p.Thr200Arg
  • NC_000023.10:g.19373555C>G
  • NM_000284.3:c.692C>G
Protein change:
T200R
Links:
dbSNP: rs1272572107
NCBI 1000 Genomes Browser:
rs1272572107
Molecular consequence:
  • NM_000284.4:c.692C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173454.2:c.806C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173455.2:c.713C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001173456.2:c.599C>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000945455Invitaecriteria provided, single submitter
Uncertain significance
(Jul 31, 2018)
germlineclinical testing

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

SCV001149874Institute of Human Genetics, Klinikum rechts der Isarcriteria provided, single submitter
Likely pathogenic
(Feb 9, 2018)
de novoclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyes1not providednot provided1not providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000945455.1

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

Description

This sequence change replaces threonine with arginine at codon 231 of the PDHA1 protein (p.Thr231Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PDHA1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. The observation of one or more missense substitutions at this codon (p.Thr231Ala and p.Thr231Lys) in affected individuals suggests that this may be a clinically significant residue (PMID: 10679936). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Institute of Human Genetics, Klinikum rechts der Isar, SCV001149874.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyes1bloodnot provided1not providednot providednot provided

Last Updated: Nov 27, 2021

Support Center