rs1554989996

Variant names:

• chr11-34978123-GATGACATTAAAGTATCAGTAAATGATTTTATCATCAAGGCAGCAGCTGTTACCCTTAAA-G
• rs1554989996
• NM_003477.3:c.965_1023delATGACATTAAAGTATCAGTAAATGATTTTATCATCAAGGCAGCAGCTGTTACCCTTAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PP5

The NM_003477.3(PDHX):​c.965_1023delATGACATTAAAGTATCAGTAAATGATTTTATCATCAAGGCAGCAGCTGTTACCCTTAAA variant causes a exon loss, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDHX NM_003477.3 exon_loss, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.38
• Publications: 0 publications found

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
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pyruvate dehydrogenase E3-binding protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-34978123-GATGACATTAAAGTATCAGTAAATGATTTTATCATCAAGGCAGCAGCTGTTACCCTTAAA-G is Pathogenic according to our data. Variant chr11-34978123-GATGACATTAAAGTATCAGTAAATGATTTTATCATCAAGGCAGCAGCTGTTACCCTTAAA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2112.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003477.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHX	NM_003477.3	MANE Select	c.965_1023delATGACATTAAAGTATCAGTAAATGATTTTATCATCAAGGCAGCAGCTGTTACCCTTAAA		exon_loss splice_region	Exon 8 of 11	NP_003468.2	O00330-1
	PDHX	NM_001135024.2		c.785_843delATGACATTAAAGTATCAGTAAATGATTTTATCATCAAGGCAGCAGCTGTTACCCTTAAA		exon_loss splice_region	Exon 8 of 11	NP_001128496.2	A0A8C8MSB2
	PDHX	NM_001166158.2		c.343-6446_343-6388delATGACATTAAAGTATCAGTAAATGATTTTATCATCAAGGCAGCAGCTGTTACCCTTAAA		intron	N/A	NP_001159630.1	O00330-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHX	ENST00000227868.9	TSL:1 MANE Select	c.965-12_1011delATGACATTAAAGTATCAGTAAATGATTTTATCATCAAGGCAGCAGCTGTTACCCTTAAA	p.Asp322fs	frameshift splice_acceptor splice_region intron	Exon 8 of 11	ENSP00000227868.4	O00330-1
	PDHX	ENST00000885501.1		c.965-12_1011delATGACATTAAAGTATCAGTAAATGATTTTATCATCAAGGCAGCAGCTGTTACCCTTAAA	p.Asp322fs	frameshift splice_acceptor splice_region intron	Exon 8 of 12	ENSP00000555560.1
	PDHX	ENST00000952507.1		c.965-12_1011delATGACATTAAAGTATCAGTAAATGATTTTATCATCAAGGCAGCAGCTGTTACCCTTAAA	p.Asp322fs	frameshift splice_acceptor splice_region intron	Exon 8 of 11	ENSP00000622566.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Pyruvate dehydrogenase E3-binding protein deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.4
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554989996; hg19: chr11-34999670;