rs2229137

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

2
3
11

Clinical Significance

Benign reviewed by expert panel P:1B:10

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]

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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
PDHA1NM_000284.4 linkc.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
PDHA1ENST00000422285.7 linkc.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.:
86
Cov.:
23
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.:
28
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.:
85
Cov.:
23
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:
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:1Benign:10
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:1Benign:2
Aug 15, 2017
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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. -

not specified Benign:3
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. -

Nov 02, 2016
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
T
BayesDel_noAF
Pathogenic
0.25
CADD
Benign
21
DANN
Benign
0.91
DEOGEN2
Uncertain
0.54
.;.;.;D;T
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.75
T;T;T;T;D
MetaRNN
Benign
0.0030
T;T;T;T;T
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
-1.0
.;.;.;N;.
PrimateAI
Uncertain
0.71
T
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
T
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.

Other links and lift over

dbSNP: rs2229137; hg19: chrX-19375782; COSMIC: COSV58826890; COSMIC: COSV58826890; API