rs863224150

Variant names:

• chrX-19353169-C-T
• rs863224150
• NM_000284.4:c.506C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PS2 PM1 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The c.506C>T variant in the PDHA1 gene is a missense mutation occurring in a hotspot domain (aa position A169, located in α β heterodimer interface (PM1). This variant is absent from population databases (PM2). This variant has been reported in three individuals in the literature with presentations consistent with PDHA1-related disease. These three cases include two assumed de novo cases (PMID:20002461 and PMID:21914562), and one maternity confirmed de novo case via exome sequencing in PMID:31683770 (PS2). PMID:20002461 Western Blot studies showed reduced E1a, and Imbard et al 2011 PDC studies indicate activity <3rd percentile in fibroblasts (PP4). In silico predictors suggest a deleterious effect (REVEL score – 0.946; PP3). In summary, this variant meets criteria to be classified as a pathogenic of PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PM1, PM2, PS2, PP3, PP4). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/6/2021. LINK:https://erepo.genome.network/evrepo/ui/classification/CA323959/MONDO:0019169/014

• Frequency: Genomes: not found (cov: 23)
• Consequence: PDHA1 NM_000284.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.51
• Publications: 8 publications found

Genes affected

PDHA1 (HGNC:8806): (pyruvate dehydrogenase E1 subunit alpha 1) The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

PDHA1 Gene-Disease associations (from GenCC):

• pyruvate dehydrogenase E1-alpha deficiency

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

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000284.4. 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
	PDHA1	NM_000284.4	MANE Select	c.506C>T	p.Ala169Val	missense	Exon 5 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.620C>T	p.Ala207Val	missense	Exon 6 of 12	NP_001166925.1	P08559-4
	PDHA1	NM_001173455.2		c.527C>T	p.Ala176Val	missense	Exon 5 of 11	NP_001166926.1	P08559-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.506C>T	p.Ala169Val	missense	Exon 5 of 11	ENSP00000394382.2	P08559-1
	PDHA1	ENST00000947567.1		c.704C>T	p.Ala235Val	missense	Exon 7 of 13	ENSP00000617626.1
	PDHA1	ENST00000947577.1		c.620C>T	p.Ala207Val	missense	Exon 6 of 12	ENSP00000617636.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Pyruvate dehydrogenase E1-alpha deficiency (3)
1	-	-	not provided (1)
1	-	-	Pyruvate dehydrogenase complex deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		7.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.95		Loss of helix (P = 0.1299)
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		1.0
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs863224150; hg19: chrX-19371287; COSMIC: COSV63327911; COSMIC: COSV63327911;