X-19344066-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000284.4(PDHA1):c.29G>C(p.Arg10Pro) 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 (no stars). Synonymous variant affecting the same amino acid position (i.e. R10R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: PDHA1 NM_000284.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.92

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant X-19344066-G-C is Pathogenic according to our data. Variant chrX-19344066-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 10887.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.29G>C	p.Arg10Pro	missense_variant	1/11	ENST00000422285.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHA1	ENST00000422285.7	c.29G>C	p.Arg10Pro	missense_variant	1/11	1	NM_000284.4	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1995

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Uncertain	25
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.80	T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M;M;M;.;.;M;.;.
MutationTaster	Benign	0.76	A;A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.13	T;T;T;D;D;T;D;D
Sift4G	Uncertain	0.032	D;D;D;D;T;D;D;D
Polyphen		0.44	.;.;.;.;.;B;.;.
Vest4		0.61
MutPred		0.84		Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);Loss of MoRF binding (P = 0.0036);
MVP		1.0
MPC		2.6
ClinPred		0.96	D
GERP RS		3.1
Varity_R		0.67
gMVP		0.54

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: rs137853257; hg19: chrX-19362184;