X-19358920-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000284.4(PDHA1):c.904C>T(p.Arg302Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R302H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

PDHA1
NM_000284.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.50

Publications

14 publications found

Variant links:

Genes affected

PDHA1 (HGNC:8806): (pyruvate dehydrogenase E1 subunit alpha 1) The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

PDHA1 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
pyruvate dehydrogenase E1-alpha deficiency
Inheritance: XL, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PDHA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-19358921-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 419850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant X-19358920-C-T is Pathogenic according to our data. Variant chrX-19358920-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHA1	NM_000284.4 link	c.904C>T	p.Arg302Cys	missense_variant	Exon 10 of 11	ENST00000422285.7	NP_000275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7 link	c.904C>T	p.Arg302Cys	missense_variant	Exon 10 of 11	1	NM_000284.4	ENSP00000394382.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1040169

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

320259

African (AFR)

AF:

0.00

AC:

AN:

25253

American (AMR)

AF:

0.00

AC:

AN:

35147

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19042

East Asian (EAS)

AF:

0.00

AC:

AN:

30001

South Asian (SAS)

AF:

0.00

AC:

AN:

52858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40493

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3981

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

789247

Other (OTH)

AF:

0.00

AC:

AN:

44147

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency

Pathogenic:6

Dec 29, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 22, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Sep 06, 2018

Genomic Medicine Lab, University of California San Francisco

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Jul 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 302 of the PDHA1 protein (p.Arg302Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pyruvate dehydrogenase deficiency (PMID: 1293379, 9671272, 20002461, 21846590, 26865159). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 10879). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PDHA1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PDHA1 function (PMID: 9671272, 21846590). For these reasons, this variant has been classified as Pathogenic.

May 08, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar; Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. The p.(Arg302His) variant has been classified as pathogenic by multiple clinical laboratories in ClinVar; Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change; This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). Additional information: Variant is predicted to result in a missense amino acid change from arginine to cysteine; This variant is heterozygous; This gene is associated with X-linked dominant disease. Affected males have been reported with variants shown to cause partial enzyme deficiency, however, variants causing a severe enzyme deficiency are presumed to be embryonically lethal (PMID: 22142326); Variant is located in the annotated dehydrogenase E1 component domain (DECIPHER); Loss of function is a known mechanism of disease in this gene and is associated with pyruvate dehydrogenase E1-alpha deficiency (MIM#312170). - Variants in this gene are known to have variable expressivity. Depending on the residual enzymatic activity, the severity of phenotypic presentation can vary. Additionally, the severity in females is dependent on X-chromosome inactivation patterns (OMIM, PMID: 22142326).

not provided

Pathogenic:2

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PDHA1: PS2, PM1, PM2, PM5, PS4:Moderate, PP2, PP3, PS3:Supporting

Jun 28, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that colonies harboring the R302C variant had no functional enzyme activity (Drakulic et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27864847, 21846590, 25495354, 25525159, 26865159, 9671272, 1293379, 31658717, 31665995, 20002461, 29445841, 35261462)

PDHA1-related disorder

Pathogenic:1

Feb 22, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PDHA1 c.1018C>T variant is predicted to result in the amino acid substitution p.Arg340Cys. This variant, also known as c.904C>T, p.Arg302Cys in the transcript NM_000284.4, has been reported to be causative for pyruvate dehydrogenase deficiency (Quintana et al. 2009. PubMed ID: 20002461; Glushakova et al. 2011. PubMed ID: 21846590; Parrini et al. 2017. PubMed ID: 27864847; Pirot et al. 2016. PubMed ID: 26865159; Stranneheim et al. 2014. PubMed ID: 25495354). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

Inborn genetic diseases

Pathogenic:1

Apr 07, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.73

BayesDel_noAF

Pathogenic

0.81

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0

.;.;.;D;D

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.0

.;.;.;H;.

PhyloP100

7.5

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.4

D;D;D;D;D

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.94

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.99

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over