rs137853259

Variant names:

• chrX-19355713-C-G
• rs137853259
• NM_000284.4:c.787C>G
• PDHA1 p.Arg263Gly

Your query was ambiguous. Multiple possible variants found:

• chrX-19355713-C-G
• chrX-19355713-C-T
• chrX-19355713-C-A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000284.4(PDHA1):​c.787C>G​(p.Arg263Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000252030: Published functional studies, including enzymatic activity and immunoblot studies, demonstrate that pyruvate dehydrogenase is affected (Wexler et al., 1992)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R263P) has been classified as Likely pathogenic. The gene PDHA1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 25)
• Consequence: PDHA1 NM_000284.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.80
• Publications: 23 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• 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: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000252030: Published functional studies, including enzymatic activity and immunoblot studies, demonstrate that pyruvate dehydrogenase is affected (Wexler et al., 1992); PMID: 19852779, 21846590, 1301207, 19639391, 30634555, 31130284, 33619735, 1508605, 9187674
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000284.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-19355714-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1184474.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-19355713-C-G is Pathogenic according to our data. Variant chrX-19355713-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 10878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.787C>G	p.Arg263Gly	missense	Exon 8 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.901C>G	p.Arg301Gly	missense	Exon 9 of 12	NP_001166925.1	P08559-4
	PDHA1	NM_001173455.2		c.808C>G	p.Arg270Gly	missense	Exon 8 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.787C>G	p.Arg263Gly	missense	Exon 8 of 11	ENSP00000394382.2	P08559-1
	PDHA1	ENST00000947567.1		c.985C>G	p.Arg329Gly	missense	Exon 10 of 13	ENSP00000617626.1
	PDHA1	ENST00000947577.1		c.946C>G	p.Arg316Gly	missense	Exon 9 of 12	ENSP00000617636.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 25

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Pyruvate dehydrogenase E1-alpha deficiency (5)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		1.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
PromoterAI		0.035	Neutral
Varity_R		0.99
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs137853259;

hg19: chrX-19373831;