rs35560997

Variant names:

• chr11-34978135-G-A
• rs35560997
• NM_003477.3:c.976G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-34978135-G-A
• chr11-34978135-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003477.3(PDHX):​c.976G>A​(p.Val326Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,506 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V326L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PDHX NM_003477.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.16
• 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
• 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)

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHX	NM_003477.3	c.976G>A	p.Val326Ile	missense_variant	Exon 8 of 11	ENST00000227868.9	NP_003468.2
PDHX	NM_001135024.2	c.796G>A	p.Val266Ile	missense_variant	Exon 8 of 11		NP_001128496.2
PDHX	XM_011520390.2	c.796G>A	p.Val266Ile	missense_variant	Exon 8 of 11		XP_011518692.1
PDHX	NM_001166158.2	c.343-6435G>A		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.976G>A	p.Val326Ile	missense_variant	Exon 8 of 11	1	NM_003477.3	ENSP00000227868.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399506 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 699594

African (AFR) AF: 0.00 AC: 0 AN: 32592

American (AMR) AF: 0.00 AC: 0 AN: 44382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25700

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39270

South Asian (SAS) AF: 0.00 AC: 0 AN: 84430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1055986

Other (OTH) AF: 0.00 AC: 0 AN: 58164

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.22	.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	.;L
PhyloP100		7.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.56	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.93	.;P
Vest4		0.39
MutPred		0.56		.;Gain of sheet (P = 0.0827);
MVP		0.37
MPC		0.27
ClinPred		0.87	D
GERP RS		5.7
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.40
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs35560997; hg19: chr11-34999682;