11-34978135-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003477.3(PDHX):c.976G>C(p.Val326Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00689 in 1,551,262 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 42 hom. )

Consequence

PDHX
NM_003477.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 7.16

Publications

12 publications found

Variant links:

Genes affected

PDHX (HGNC:21350): (pyruvate dehydrogenase complex component X) The pyruvate dehydrogenase (PDH) complex is located in the mitochondrial matrix and catalyzes the conversion of pyruvate to acetyl coenzyme A. The PDH complex thereby links glycolysis to Krebs cycle. The PDH complex contains three catalytic subunits, E1, E2, and E3, two regulatory subunits, E1 kinase and E1 phosphatase, and a non-catalytic subunit, E3 binding protein (E3BP). This gene encodes the E3 binding protein subunit; also known as component X of the pyruvate dehydrogenase complex. This protein tethers E3 dimers to the E2 core of the PDH complex. Defects in this gene are a cause of pyruvate dehydrogenase deficiency which results in neurological dysfunction and lactic acidosis in infancy and early childhood. This protein is also a minor antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with the autoimmune liver disease primary biliary cirrhosis (PBC). In PBC, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. PBC eventually leads to cirrhosis and liver failure. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]

PDHX Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
pyruvate dehydrogenase E3-binding protein deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

PDHX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014632463).

BP6

Variant 11-34978135-G-C is Benign according to our data. Variant chr11-34978135-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00574 (874/152212) while in subpopulation NFE AF = 0.00975 (663/67992). AF 95% confidence interval is 0.00914. There are 4 homozygotes in GnomAd4. There are 431 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PDHX	NM_003477.3 link	c.976G>C	p.Val326Leu	missense_variant	Exon 8 of 11	ENST00000227868.9	NP_003468.2
PDHX	NM_001135024.2 link	c.796G>C	p.Val266Leu	missense_variant	Exon 8 of 11		NP_001128496.2
PDHX	XM_011520390.2 link	c.796G>C	p.Val266Leu	missense_variant	Exon 8 of 11		XP_011518692.1
PDHX	NM_001166158.2 link	c.343-6435G>C		intron_variant	Intron 3 of 5		NP_001159630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHX	ENST00000227868.9 link	c.976G>C	p.Val326Leu	missense_variant	Exon 8 of 11	1	NM_003477.3	ENSP00000227868.4

Frequencies

GnomAD3 genomes

AF:

0.00575

AC:

874

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00387

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00415

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00975

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00621

AC:

1549

AN:

249402

AF XY:

0.00624

show subpopulations

Gnomad AFR exome

AF:

0.00155

Gnomad AMR exome

AF:

0.00251

Gnomad ASJ exome

AF:

0.00429

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00542

Gnomad NFE exome

AF:

0.00996

Gnomad OTH exome

AF:

0.00559

GnomAD4 exome

AF:

0.00701

AC:

9810

AN:

1399050

Hom.:

Cov.:

AF XY:

0.00709

AC XY:

4960

AN XY:

699382

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

32590

American (AMR)

AF:

0.00246

AC:

109

AN:

44382

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

111

AN:

25696

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39270

South Asian (SAS)

AF:

0.00474

AC:

400

AN:

84426

European-Finnish (FIN)

AF:

0.00576

AC:

307

AN:

53338

Middle Eastern (MID)

AF:

0.00390

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

0.00806

AC:

8508

AN:

1055552

Other (OTH)

AF:

0.00537

AC:

312

AN:

58154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

394

787

1181

1574

1968

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

288

576

864

1152

1440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00574

AC:

874

AN:

152212

Hom.:

Cov.:

AF XY:

0.00579

AC XY:

431

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

41538

American (AMR)

AF:

0.00386

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00353

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00415

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00975

AC:

663

AN:

67992

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00869

Hom.:

Bravo

AF:

0.00539

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00886

AC:

ExAC

AF:

0.00641

AC:

778

Asia WGS

AF:

0.00347

AC:

AN:

3468

EpiCase

AF:

0.00890

EpiControl

AF:

0.00853

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PDHX: BS2 -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jan 13, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 14, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pyruvate dehydrogenase E3-binding protein deficiency

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pyruvate dehydrogenase E1-alpha deficiency

Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PDHX-related disorder

Benign:1

Mar 19, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.28

.;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.77

.;N

PhyloP100

7.2

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.20

Sift

Benign

0.30

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.93

.;P

Vest4

0.61

MutPred

0.58

.;Loss of methylation at K325 (P = 0.067);

MVP

0.53

MPC

0.25

ClinPred

0.020

GERP RS

5.7

PromoterAI

-0.0079

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.72

Mutation Taster

=21/79

disease causing

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over