11-34966740-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_003477.3(PDHX):c.742C>T(p.Gln248*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q248Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PDHX
NM_003477.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.72

Publications

4 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-34966740-C-T is Pathogenic according to our data. Variant chr11-34966740-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2118.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
PDHX	NM_003477.3 link	c.742C>T	p.Gln248*	stop_gained	Exon 6 of 11	ENST00000227868.9	NP_003468.2	O00330-1
PDHX	NM_001135024.2 link	c.562C>T	p.Gln188*	stop_gained	Exon 6 of 11		NP_001128496.2	O00330
PDHX	XM_011520390.2 link	c.562C>T	p.Gln188*	stop_gained	Exon 6 of 11		XP_011518692.1	A0A8C8MSB2
PDHX	NM_001166158.2 link	c.343-17830C>T		intron_variant	Intron 3 of 5		NP_001159630.1	O00330-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PDHX	ENST00000227868.9 link	c.742C>T	p.Gln248*	stop_gained	Exon 6 of 11	1	NM_003477.3	ENSP00000227868.4	O00330-1
PDHX	ENST00000448838.8 link	c.562C>T	p.Gln188*	stop_gained	Exon 6 of 11	5		ENSP00000389404.3	A0A8C8MSB2
PDHX	ENST00000430469.6 link	c.343-17830C>T		intron_variant	Intron 3 of 5	2		ENSP00000415695.2	O00330-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251348

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111976

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.0000192

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyruvate dehydrogenase E3-binding protein deficiency

Pathogenic:3

Feb 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 23, 2023

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This homozygous termination (stop-gain) [PVS1] variant is identified in a 7 year male with neonatal seizures, polydactyly and later developed severe ID with microcephaly. Metabolic acidosis and increased lactate. MRI brain: periventricular leukomalacia. This nucleotide change is absent in gnomAD database [PM2]. Insilico prediction [MutationTaster] predicts a deleterious nature of this variant. A clinvar entry for this variant is available [Variation ID: 2881] with an interpretation of “Pathogenic” [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic" -

Jan 23, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PVS1,PM3,PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.16

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.16

PhyloP100

1.7

Vest4

0.71

GERP RS

3.6

Mutation Taster

=7/193

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over