chr11-34966740-C-T

Variant names:

• chr11-34966740-C-T
• rs113309941
• NM_003477.3:c.742C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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 (★★). 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.72

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id 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	c.742C>T	p.Gln248*	stop_gained	Exon 6 of 11	ENST00000227868.9	NP_003468.2
PDHX	NM_001135024.2	c.562C>T	p.Gln188*	stop_gained	Exon 6 of 11		NP_001128496.2
PDHX	XM_011520390.2	c.562C>T	p.Gln188*	stop_gained	Exon 6 of 11		XP_011518692.1
PDHX	NM_001166158.2	c.343-17830C>T		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	c.742C>T	p.Gln248*	stop_gained	Exon 6 of 11	1	NM_003477.3	ENSP00000227868.4
PDHX	ENST00000448838.8	c.562C>T	p.Gln188*	stop_gained	Exon 6 of 11	5		ENSP00000389404.3
PDHX	ENST00000430469.6	c.343-17830C>T		intron_variant	Intron 3 of 5	2		ENSP00000415695.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251348 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135828

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 SAS 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: 24 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000267 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate dehydrogenase E3-binding protein deficiency Pathogenic:3

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 -

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" -

Feb 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.16	N
Vest4		0.71
GERP RS		3.6

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

LitVar

Other links and lift over

dbSNP: rs113309941; hg19: chr11-34988287;