rs2229137

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-19357664-A-C
• chrX-19357664-A-T

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:12
• 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):

• pyruvate dehydrogenase E1-alpha deficiency

  Inheritance: AR, XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for PDHA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

Sel.	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	P08559-1
	PDHA1	NM_001173454.2		c.958A>C	p.Met320Leu	missense	Exon 10 of 12	NP_001166925.1	P08559-4
	PDHA1	NM_001173455.2		c.865A>C	p.Met289Leu	missense	Exon 9 of 11	NP_001166926.1	P08559-2

Ensembl Transcripts

Sel.	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	P08559-1
	PDHA1	ENST00000947567.1		c.1042A>C	p.Met348Leu	missense	Exon 11 of 13	ENSP00000617626.1
	PDHA1	ENST00000947577.1		c.1003A>C	p.Met335Leu	missense	Exon 10 of 12	ENSP00000617636.1

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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
1	-	3	Pyruvate dehydrogenase E1-alpha deficiency (4)
-	-	2	not provided (2)
-	-	2	Pyruvate dehydrogenase complex deficiency (2)
-	-	1	Inborn genetic diseases (1)

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;