NM_000284.4(PDHA1):c.506C>T (p.Ala169Val) AND Pyruvate dehydrogenase E1-alpha deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 9, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000640506.10

Allele description [Variation Report for NM_000284.4(PDHA1):c.506C>T (p.Ala169Val)]

NM_000284.4(PDHA1):c.506C>T (p.Ala169Val)

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.506C>T (p.Ala169Val)

Other names:

p.A169V:GCG>GTG

HGVS:

NC_000023.11:g.19353169C>T
NG_016781.1:g.14277C>T
NM_000284.4:c.506C>TMANE SELECT
NM_001173454.2:c.620C>T
NM_001173455.2:c.527C>T
NM_001173456.2:c.506C>T
NP_000275.1:p.Ala169Val
NP_001166925.1:p.Ala207Val
NP_001166926.1:p.Ala176Val
NP_001166927.1:p.Ala169Val
NP_001166927.1:p.Ala169Val
NC_000023.10:g.19371287C>T
NC_000023.10:g.19371287C>T
NM_000284.3:c.506C>T
NM_000284.4(PDHA1):c.506C>TMANE SELECT
NM_001173456.1:c.506C>T
p.Ala169Val

Protein change:

A169V

Links:

dbSNP: rs863224150

NCBI 1000 Genomes Browser:

rs863224150

Molecular consequence:

NM_000284.4:c.506C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173454.2:c.620C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173455.2:c.527C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173456.2:c.506C>T - 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

Recent activity

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Taxonomy Links for Protein (Select 2462537005) (1)
Taxonomy
serine/threonine-protein kinase Nek5 isoform X3 [Homo sapiens]
serine/threonine-protein kinase Nek5 isoform X3 [Homo sapiens]
gi|2217294208|ref|XP_047286245.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000762098	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 13, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20002461, 21914562, 28492532
SCV005016501	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 9, 2023)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000762098

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 13, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV005016501

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 9, 2023)

de novo

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency.

Quintana E, Gort L, Busquets C, Navarro-Sastre A, Lissens W, Moliner S, Lluch M, Vilaseca MA, De Meirleir L, Ribes A, Briones P; PDH Working Group..

Clin Genet. 2010 May;77(5):474-82. doi: 10.1111/j.1399-0004.2009.01313.x. Epub 2009 Dec 10. Erratum in: Clin Genet. 2010 Jul;78(1):101.

PubMed [citation]

PMID:: 20002461

Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency. Structural implications of novel amino acid substitutions in E1 protein.

Imbard A, Boutron A, Vequaud C, Zater M, de Lonlay P, de Baulny HO, Barnerias C, Miné M, Marsac C, Saudubray JM, Brivet M.

Mol Genet Metab. 2011 Dec;104(4):507-16. doi: 10.1016/j.ymgme.2011.08.008. Epub 2011 Aug 18.

PubMed [citation]

PMID:: 21914562

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000762098.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in several individuals affected with PDHA1-related disease, and found to be de novo in one of these cases (PMID: 20002461, 21914562, Invitae). ClinVar contains an entry for this variant (Variation ID: 214941). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 169 of the PDHA1 protein (p.Ala169Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine.

#	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

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV005016501.1

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

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

Last Updated: Sep 29, 2024

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