NM_000284.4:c.1132C>T

Variant names:

• chrX-19359612-C-T
• rs863224147
• NM_000284.4:c.1132C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3 PP4 PM6_Strong

This summary comes from the ClinGen Evidence Repository: The c.1132C>T (p.R378C) variant in PDHA1 has been reported in multiples males and females with pyruvate dehydrogenase deficiency and is one of the more common pathogenic variants seen in this cohort (PMID:22896851). It has been seen in at least three individuals with decreased pyruvate dehydrogenase activity (PP4; Patient 6 in PMID:8962591; Subject M-7 in PMID:20002461; Subject 35-2 in PMID:10679936). This variant has been identified as a de novo occurrence (unconfirmed parental relationships) in at least 4 unrelated individuals with pyruvate dehydrogenase deficiency [PM6_Strong; utilized ClinGen SVI de novo scoring guidance (phenotype consistent but not highly specific); PMID:10679936, subject 35-2; PMID:20002461, subject M-7; PMID:21914562, subject AM8; PMID:21914562, subject AF22]. Of note, to our knowledge, there are no reports of this variant being inherited from a healthy mother, however it is important to note that not all cases reported in the literature had mothers who were tested. This variant is absent from gnomAD v2.1.1 (PM2). Another missense variant at this position [c.1133G>A, p.R378H] has been reported in at least six other probands (PM5; PMIDs: 8032855 - 1 case, 7887409 - 2 cases, 9409363 - 3 cases) and is a known pathogenic variant. The computational predictor REVEL gives a score of 0.907, which is above the threshold of 0.75, evidence that correlates with impact to PDHA1 function (PP3). In summary, this variant meets criteria to be classified as pathogenic for pyruvate dehydrogenase deficiency inherited in an X-linked manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on May 20, 2020. PDHA1-specific ACMG/AMP criteria applied: PM2, PM5, PM6_strong, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA323094/MONDO:0019169/014

• Frequency: Genomes: not found (cov: 22)
• Consequence: PDHA1 NM_000284.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 5.70
• Publications: 14 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):

• Leigh syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• pyruvate dehydrogenase E1-alpha deficiency

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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.1132C>T	p.Arg378Cys	missense	Exon 11 of 11	NP_000275.1
	PDHA1	NM_001173454.2		c.1246C>T	p.Arg416Cys	missense	Exon 12 of 12	NP_001166925.1
	PDHA1	NM_001173455.2		c.1153C>T	p.Arg385Cys	missense	Exon 11 of 11	NP_001166926.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.1132C>T	p.Arg378Cys	missense	Exon 11 of 11	ENSP00000394382.2
	PDHA1	ENST00000947567.1		c.1330C>T	p.Arg444Cys	missense	Exon 13 of 13	ENSP00000617626.1
	PDHA1	ENST00000947577.1		c.1291C>T	p.Arg431Cys	missense	Exon 12 of 12	ENSP00000617636.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Pyruvate dehydrogenase E1-alpha deficiency (6)
1	-	-	not provided (1)
1	-	-	Pyruvate dehydrogenase complex deficiency (1)
1	-	-	SUDDEN INFANT DEATH SYNDROME (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.88		Loss of MoRF binding (P = 0.002)
MVP		0.99
MPC		0.052
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.88
Mutation Taster		=0/100	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: rs863224147; hg19: chrX-19377730; COSMIC: COSV58825380; COSMIC: COSV58825380;