NM_000284.4(PDHA1):c.491A>G (p.Asn164Ser) AND Pyruvate dehydrogenase complex deficiency

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 13, 2022
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:: RCV001824834.2

Allele description [Variation Report for NM_000284.4(PDHA1):c.491A>G (p.Asn164Ser)]

NM_000284.4(PDHA1):c.491A>G (p.Asn164Ser)

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.491A>G (p.Asn164Ser)

HGVS:

NC_000023.11:g.19353154A>G
NG_016781.1:g.14262A>G
NM_000284.4:c.491A>GMANE SELECT
NM_001173454.2:c.605A>G
NM_001173455.2:c.512A>G
NM_001173456.2:c.491A>G
NP_000275.1:p.Asn164Ser
NP_001166925.1:p.Asn202Ser
NP_001166926.1:p.Asn171Ser
NP_001166927.1:p.Asn164Ser
NC_000023.10:g.19371272A>G
NM_000284.3:c.491A>G

Protein change:

N164S

Links:

dbSNP: rs1555933963

NCBI 1000 Genomes Browser:

rs1555933963

Molecular consequence:

NM_000284.4:c.491A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001173454.2:c.605A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001173455.2:c.512A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001173456.2:c.491A>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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002074233	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 13, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23021068, 10679936, 28918066 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002074233

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 13, 2022)

germline

clinical testing

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

Citation Link

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

Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype.

DeBrosse SD, Okajima K, Zhang S, Nakouzi G, Schmotzer CL, Lusk-Kopp M, Frohnapfel MB, Grahame G, Kerr DS.

Mol Genet Metab. 2012 Nov;107(3):394-402. doi: 10.1016/j.ymgme.2012.09.001. Epub 2012 Sep 7.

PubMed [citation]

PMID:: 23021068

Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency.

Lissens W, De Meirleir L, Seneca S, Liebaers I, Brown GK, Brown RM, Ito M, Naito E, Kuroda Y, Kerr DS, Wexler ID, Patel MS, Robinson BH, Seyda A.

Hum Mutat. 2000;15(3):209-19. Review.

PubMed [citation]

PMID:: 10679936

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002074233.1

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

Description

Variant summary: PDHA1 c.491A>G (p.Asn164Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183518 control chromosomes (gnomAD). c.491A>G has been reported in the literature in multiple male individuals affected with Pyruvate Dehydrogenase Deficiency (e.g. Lissens_2000, DeBrosse_2012, Shin_2017). These data indicate that the variant is very likely to be associated with disease. These publications also reported enzymatic measurements from patient derived fibroblasts, and demonstrated low activities (Lissens_2000, Shin_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: Oct 20, 2024

ClinVar

Relating variation to medicine