rs863224147

Positions:

• chrX-19359612-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM6_Strong PM2 PM5 PP3 PP4

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:7
• Conservation: PhyloP100: 5.70

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]

ACMG classification

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDHA1	NM_000284.4	c.1132C>T	p.Arg378Cys	missense_variant	11/11	ENST00000422285.7	NP_000275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7	c.1132C>T	p.Arg378Cys	missense_variant	11/11	1	NM_000284.4	ENSP00000394382	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2022	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDHA1 protein function. ClinVar contains an entry for this variant (Variation ID: 214936). This missense change has been observed in individual(s) with pyruvate dehydrogenase lipoic acid synthetase deficiency (PMID: 8962591, 20002125, 20002461, 24718837, 28639102). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 378 of the PDHA1 protein (p.Arg378Cys). -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jun 07, 2017	This missense variant in the PDHA1 gene was identified in a female patient with developmental delay and neurological disorder. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 20, 2018	- -

Pyruvate dehydrogenase complex deficiency Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Oct 25, 2021

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. -

SUDDEN INFANT DEATH SYNDROME Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Robert's Program, Boston Children's Hospital

Oct 01, 2021

We classify this variant as pathogenic using the following ACMG/AMP criteria: PS3, PM2, PP1, PP2, PP5 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 24, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20002461, 10679936, 28639102, 27629047, 31665838, 8962591, 32005694, 33092611, 33914258, 32445240, 34052969, 35027292, 35094435, 36675121, 33588022) -

Computational scores

Source: dbNSFP v4.3

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;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.1	.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224147; hg19: chrX-19377730; COSMIC: COSV58825380; COSMIC: COSV58825380;