NM_000284.4(PDHA1):c.934_992dup (p.Ser331delinsArgValArgValThrLeuLeuCysPheSerArgThrGlyTrpTer) AND Pyruvate dehydrogenase E1-alpha deficiency

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 11, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000793164.6

Allele description [Variation Report for NM_000284.4(PDHA1):c.934_992dup (p.Ser331delinsArgValArgValThrLeuLeuCysPheSerArgThrGlyTrpTer)]

NM_000284.4(PDHA1):c.934_992dup (p.Ser331delinsArgValArgValThrLeuLeuCysPheSerArgThrGlyTrpTer)

Gene:

PDHA1:pyruvate dehydrogenase E1 subunit alpha 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

Xp22.12

Genomic location:

Preferred name:

NM_000284.4(PDHA1):c.934_992dup (p.Ser331delinsArgValArgValThrLeuLeuCysPheSerArgThrGlyTrpTer)

HGVS:

NC_000023.11:g.19358950_19359008dup
NG_016781.1:g.20058_20116dup
NG_021184.1:g.161254_161312dup
NM_000284.4:c.934_992dupMANE SELECT
NM_001173454.2:c.1048_1106dup
NM_001173455.2:c.955_1013dup
NM_001173456.2:c.841_899dup
NP_000275.1:p.Ser331delinsArgValArgValThrLeuLeuCysPheSerArgThrGlyTrpTer
NP_001166925.1:p.Ser369delinsArgValArgValThrLeuLeuCysPheSerArgThrGlyTrpTer
NP_001166926.1:p.Ser338delinsArgValArgValThrLeuLeuCysPheSerArgThrGlyTrpTer
NP_001166927.1:p.Ser300delinsArgValArgValThrLeuLeuCysPheSerArgThrGlyTrpTer
NC_000023.10:g.19377067_19377068insAGTAAGAGTGACCCTATTATGCTTCTCAAGGACAGGATGGTGAACAGCAATCTTGCCAG
NC_000023.10:g.19377068_19377126dup
NM_000284.3:c.934_992dup

Links:

dbSNP: rs1602231539

NCBI 1000 Genomes Browser:

rs1602231539

Molecular consequence:

NM_000284.4:c.934_992dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001173454.2:c.1048_1106dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001173455.2:c.955_1013dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001173456.2:c.841_899dup - nonsense - [Sequence Ontology: SO:0001587]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000932505	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 11, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 1907799, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000932505

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 11, 2018)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Pyruvate dehydrogenase deficiency due to a 20-bp deletion in exon II of the pyruvate dehydrogenase (PDH) E1 alpha gene.

Chun K, MacKay N, Petrova-Benedict R, Robinson BH.

Am J Hum Genet. 1991 Aug;49(2):414-20.

PubMed [citation]

PMID:: 1907799
PMCID:: PMC1683296

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, SCV000932505.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Glu358Glyfs*12) that lies downstream of this variant has been determined to be pathogenic (PMID: 1907799). This suggests that deletion of this region of the PDHA1 protein is causative of disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. This variant has not been reported in the literature in individuals with PDHA1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the PDHA1 gene (p.Ser331Argfs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 60 amino acids of the PDHA1 protein.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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