NM_000284.4:c.844A>C

Variant names:

• chrX-19357664-A-C
• rs2229137
• NM_000284.4:c.844A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BA1 BS2

This summary comes from the ClinGen Evidence Repository: The allele frequency of the c.844A>C; p. M282L variant in the PDHA1 gene is 0.207% in gnomAD, including 1,436 hemizygotes. This allele frequency, and the frequency with which it is seen in hemizygotes in the general population are high enough to be classified as benign based on thresholds defined by the ClinGen PDHA1 Variant Curation Expert Panel (>0.092%; gnomAD >16 hemizygotes). In summary, this variant meets criteria to be classified as benign for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (BA1, BS2). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 2/16/2021. LINK:https://erepo.genome.network/evrepo/ui/classification/CA121220/MONDO:0019169/014

• Frequency:
  • Genomes: 𝑓 0.0095 (85 hom., 355 hem., cov: 23)
  • Exomes 𝑓: 0.0079 (623 hom. 2880 hem.)
• Consequence: PDHA1 NM_000284.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 B:11
• Conservation: PhyloP100: 8.92
• Publications: 19 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: Benign. The variant received -12 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHA1	NM_000284.4	MANE Select	c.844A>C	p.Met282Leu	missense	Exon 9 of 11	NP_000275.1
	PDHA1	NM_001173454.2		c.958A>C	p.Met320Leu	missense	Exon 10 of 12	NP_001166925.1
	PDHA1	NM_001173455.2		c.865A>C	p.Met289Leu	missense	Exon 9 of 11	NP_001166926.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.844A>C	p.Met282Leu	missense	Exon 9 of 11	ENSP00000394382.2
	PDHA1	ENST00000423505.6	TSL:2	c.958A>C	p.Met320Leu	missense	Exon 10 of 12	ENSP00000406473.2
	PDHA1	ENST00000417819.6	TSL:3	c.928A>C	p.Met310Leu	missense	Exon 10 of 12	ENSP00000404616.2

Frequencies

GnomAD3 genomes AF: 0.00953 AC: 1065 AN: 111782 Hom.: 86 Cov.: 23

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00436

Gnomad ASJ AF: 0.00339

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.000339

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0214 AC: 3930 AN: 183510 AF XY: 0.0191

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.00360

Gnomad EAS exome AF: 0.259

Gnomad FIN exome AF: 0.00487

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00789 AC: 8643 AN: 1095835 Hom.: 623 Cov.: 28 AF XY: 0.00797 AC XY: 2880 AN XY: 361269

African (AFR) AF: 0.000645 AC: 17 AN: 26363

American (AMR) AF: 0.000312 AC: 11 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00356 AC: 69 AN: 19376

East Asian (EAS) AF: 0.231 AC: 6989 AN: 30194

South Asian (SAS) AF: 0.00660 AC: 357 AN: 54073

European-Finnish (FIN) AF: 0.00560 AC: 227 AN: 40532

Middle Eastern (MID) AF: 0.000969 AC: 4 AN: 4129

European-Non Finnish (NFE) AF: 0.000173 AC: 145 AN: 839941

Other (OTH) AF: 0.0179 AC: 824 AN: 46023

GnomAD4 genome AF: 0.00950 AC: 1063 AN: 111837 Hom.: 85 Cov.: 23 AF XY: 0.0104 AC XY: 355 AN XY: 34039

African (AFR) AF: 0.00136 AC: 42 AN: 30771

American (AMR) AF: 0.00436 AC: 46 AN: 10553

Ashkenazi Jewish (ASJ) AF: 0.00339 AC: 9 AN: 2651

East Asian (EAS) AF: 0.247 AC: 869 AN: 3523

South Asian (SAS) AF: 0.0112 AC: 30 AN: 2672

European-Finnish (FIN) AF: 0.00377 AC: 23 AN: 6099

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 218

European-Non Finnish (NFE) AF: 0.000339 AC: 18 AN: 53146

Other (OTH) AF: 0.0151 AC: 23 AN: 1520

Alfa AF: 0.00846 Hom.: 451

Bravo AF: 0.0106

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00209 AC: 8

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.0195 AC: 2370

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:1 Benign:3

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Aug 15, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Apr 05, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:3

Nov 02, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 20, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PDHA1 c.844A>C (p.Met282Leu) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.021 in 183510 control chromosomes, predominantly at a frequency of 0.26 within the East Asian subpopulation in the gnomAD database, including 329 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 831999.87 fold of the estimated maximal expected allele frequency for a pathogenic variant in PDHA1 causing Pyruvate Dehydrogenase Deficiency phenotype (3.1e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, all but one classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

Dec 27, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Pyruvate dehydrogenase complex deficiency Benign:2

Apr 02, 2021

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The allele frequency of the c.844A>C (p.M282L) variant in the PDHA1 gene is 0.207% in gnomAD, including 1,436 hemizygotes. This allele frequency, and the frequency with which it is seen in hemizygotes in the general population are high enough to be classified as benign based on thresholds defined by the ClinGen PDHA1 Variant Curation Expert Panel (>0.092%; gnomAD >16 hemizygotes). In summary, this variant meets criteria to be classified as benign for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (BA1, BS2). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 2/16/2021.

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

May 04, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Inborn genetic diseases Benign:1

Jun 25, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-1.0	N
PhyloP100		8.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.59
Sift	Benign	0.74	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.58
MutPred		0.81		Loss of methylation at K277 (P = 0.052)
MPC		1.2
ClinPred		0.057	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.92
Mutation Taster		=108/92	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs2229137; hg19: chrX-19375782; COSMIC: COSV58826890; COSMIC: COSV58826890;