rs863224146

Variant names:

• chrX-19358926-C-T
• rs863224146
• NM_000284.4:c.910C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PVS1 PM6_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The c.910C>T; p. R304X variant in the PDHA1 gene is a nonsense mutation resulting in truncation >50bp upstream of the last exon-exon junction in PDHA1 and is predicted to undergo nonsense mediated decay (PVS1). While this mutation occurs in a hotspot domain (aa position R304, phosphorylation loop region), it is predicted to undergo nonsense mediated decay so PM1 was not scored. This variant is absent from population databases (PM2). This variant has been reported once in the literature in an 8-day old patient with neonatal lactic acidosis, microcephaly, hypotonia and psychomotor delay (PMID:21914562). The variant was not seen in patient’s mother, but maternity was not confirmed (PM6_supporting). Blood pyruvate was significantly elevated at 0.84mM with a lactate/pyruvate ratio of 19, which the PDHA1 Curation Expert Panel agreed was supportive of pathogenicity (PP4). 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: (PVS1, PM2, PM6_supporting, PP4). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 03/10/2021. LINK:https://erepo.genome.network/evrepo/ui/classification/CA321113/MONDO:0019169/014

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PDHA1 NM_000284.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 3.00
• Publications: 5 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 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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.910C>T	p.Arg304*	stop_gained	Exon 10 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.1024C>T	p.Arg342*	stop_gained	Exon 11 of 12	NP_001166925.1	P08559-4
	PDHA1	NM_001173455.2		c.931C>T	p.Arg311*	stop_gained	Exon 10 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.910C>T	p.Arg304*	stop_gained	Exon 10 of 11	ENSP00000394382.2	P08559-1
	PDHA1	ENST00000947567.1		c.1108C>T	p.Arg370*	stop_gained	Exon 12 of 13	ENSP00000617626.1
	PDHA1	ENST00000947577.1		c.1069C>T	p.Arg357*	stop_gained	Exon 11 of 12	ENSP00000617636.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1059100 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 332492

African (AFR) AF: 0.00 AC: 0 AN: 25655

American (AMR) AF: 0.00 AC: 0 AN: 35172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19160

East Asian (EAS) AF: 0.00 AC: 0 AN: 30084

South Asian (SAS) AF: 0.00 AC: 0 AN: 53308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40501

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4032

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 806373

Other (OTH) AF: 0.00 AC: 0 AN: 44815

GnomAD4 genome Cov.: 22

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)
2	-	-	not provided (2)
1	-	-	Pyruvate dehydrogenase complex deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		3.0
Vest4		0.88
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs863224146; hg19: chrX-19377044;