rs863224148

Variant names:

• chrX-19350033-C-T
• rs863224148
• NM_000284.4:c.214C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM6 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The c.214C>T (p.R72C) variant in PDHA1 has been reported in multiples males with pyruvate dehydrogenase deficiency with phenotypes ranging from childhood onset Leigh syndrome spectrum (PMID:8664900) to living into adulthood with ataxia, neuropathy, and dystonia (PMID:21914562). We did not come across any affected female case reports in this extensive literature review. This variant has been reported to be inherited from a healthy mother (PMID:10679936; case 3-4) and there have been several de novo case reports, as well. Indeed, this variant has been identified as a de novo occurrence (unconfirmed parental relationships) in at least three unrelated individuals with pyruvate dehydrogenase deficiency [PM6; Utilized ClinGen SVI de novo scoring guidance (phenotype consistent but not highly specific); PMID:10679936, case 3-2; PMID:10679936, case 3-3; PMID:21914562, case AM23]. Additionally, this variant has been seen in at least one other individual with documented decreased pyruvate dehydrogenase activity (PP4; Patient 3 in PMID:15384102 had Leigh syndrome and decreased total PDH complex activity (in native and DCA-activated states) in fibroblast cell line (<3rd percentile of controls). This variant is absent from gnomAD v2.1.1 (PM2). The computational predictor REVEL gives a score of 0.955, 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 likely 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, PM6, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA320653/MONDO:0019169/014

• Frequency: Genomes: not found (cov: 23)
• Consequence: PDHA1 NM_000284.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 2.92
• Publications: 7 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: 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.214C>T	p.Arg72Cys	missense	Exon 3 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.328C>T	p.Arg110Cys	missense	Exon 4 of 12	NP_001166925.1	P08559-4
	PDHA1	NM_001173455.2		c.214C>T	p.Arg72Cys	missense	Exon 3 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.214C>T	p.Arg72Cys	missense	Exon 3 of 11	ENSP00000394382.2	P08559-1
	PDHA1	ENST00000947567.1		c.412C>T	p.Arg138Cys	missense	Exon 5 of 13	ENSP00000617626.1
	PDHA1	ENST00000947577.1		c.328C>T	p.Arg110Cys	missense	Exon 4 of 12	ENSP00000617636.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000426 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Pyruvate dehydrogenase E1-alpha deficiency (4)
2	-	-	not provided (2)
1	-	-	Abnormality of the mitochondrion (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Pyruvate dehydrogenase complex deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	5.1	H
PhyloP100		2.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.97		Loss of MoRF binding (P = 0.0158)
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		1.0
Mutation Taster		=2/98	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: rs863224148; hg19: chrX-19368151; COSMIC: COSV63327821; COSMIC: COSV63327821;