rs2229137

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BA1BS2

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

Scores

Clinical Significance

Benign reviewed by expert panel P:1B:11

Conservation

PhyloP100: 8.92

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHA1	NM_000284.4 link	c.844A>C	p.Met282Leu	missense_variant	Exon 9 of 11	ENST00000422285.7	NP_000275.1	P08559-1A0A024RBX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7 link	c.844A>C	p.Met282Leu	missense_variant	Exon 9 of 11	1	NM_000284.4	ENSP00000394382.2		P08559-1

Frequencies

GnomAD3 genomes

AF:

0.00953

AC:

1065

AN:

111782

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

353

AN XY:

33974

show subpopulations

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

GnomAD3 exomes

AF:

0.0214

AC:

3930

AN:

183510

Hom.:

331

AF XY:

0.0191

AC XY:

1298

AN XY:

67940

show subpopulations

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 SAS exome

AF:

0.00608

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.:

AF XY:

0.00797

AC XY:

2880

AN XY:

361269

show subpopulations

Gnomad4 AFR exome

AF:

0.000645

Gnomad4 AMR exome

AF:

0.000312

Gnomad4 ASJ exome

AF:

0.00356

Gnomad4 EAS exome

AF:

0.231

Gnomad4 SAS exome

AF:

0.00660

Gnomad4 FIN exome

AF:

0.00560

Gnomad4 NFE exome

AF:

0.000173

Gnomad4 OTH exome

AF:

0.0179

GnomAD4 genome

AF:

0.00950

AC:

1063

AN:

111837

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

355

AN XY:

34039

show subpopulations

Gnomad4 AFR

AF:

0.00136

Gnomad4 AMR

AF:

0.00436

Gnomad4 ASJ

AF:

0.00339

Gnomad4 EAS

AF:

0.247

Gnomad4 SAS

AF:

0.0112

Gnomad4 FIN

AF:

0.00377

Gnomad4 NFE

AF:

0.000339

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.00958

Hom.:

414

Bravo

AF:

0.0106

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00209

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.0195

AC:

2370

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency

Pathogenic:1Benign: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

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. -

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. -

Pyruvate dehydrogenase complex deficiency

Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Uncertain

0.54

.;.;.;D;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

T;T;T;T;D

MetaRNN

Benign

0.0030

T;T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

-1.0

.;.;.;N;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.69

N;N;N;N;N

REVEL

Uncertain

0.59

Sift

Benign

0.74

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;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

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over