rs2229137

chrX-19357664-A-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000284.4(PDHA1):c.844A>C(p.Met282Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00804 in 1,207,672 control chromosomes in the GnomAD database, including 708 homozygotes. There are 3,235 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• 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:9
• Conservation: PhyloP100: 8.92

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000284.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0034937859).
• BP6: Variant X-19357664-A-C is Benign according to our data. Variant chrX-19357664-A-C is described in ClinVar as [Benign]. Clinvar id is 10885.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chrX-19357664-A-C is described in Lovd as [Likely_benign]. Variant chrX-19357664-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.844A>C	p.Met282Leu	missense_variant	9/11	ENST00000422285.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHA1	ENST00000422285.7	c.844A>C	p.Met282Leu	missense_variant	9/11	1	NM_000284.4	P1

Frequencies

GnomAD3 genomes AF: 0.00953 AC: 1065 AN: 111782 Hom.: 86 Cov.: 23 AF XY: 0.0104 AC XY: 353 AN XY: 33974

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

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

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

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:1 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 20, 2021	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2016	- -

Pyruvate dehydrogenase complex deficiency Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Apr 02, 2021	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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2015

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 04, 2016

- -

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
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
MutationTaster	Benign	0.00031	P;P;P;P;P
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

Other links and lift over

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