rs1131691584

Variant names:

• chrX-19359580-A-C
• rs1131691584
• NM_000284.4:c.1100A>C

Your query was ambiguous. Multiple possible variants found:

• chrX-19359580-A-C
• chrX-19359580-A-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_000284.4(PDHA1):​c.1100A>C​(p.His367Pro) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H367L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PDHA1 NM_000284.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.16
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-19359580-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 992815.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant X-19359580-A-C is Pathogenic according to our data. Variant chrX-19359580-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 429771.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHA1	NM_000284.4	MANE Select	c.1100A>C	p.His367Pro	missense	Exon 11 of 11	NP_000275.1
	PDHA1	NM_001173454.2		c.1214A>C	p.His405Pro	missense	Exon 12 of 12	NP_001166925.1
	PDHA1	NM_001173455.2		c.1121A>C	p.His374Pro	missense	Exon 11 of 11	NP_001166926.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.1100A>C	p.His367Pro	missense	Exon 11 of 11	ENSP00000394382.2
	PDHA1	ENST00000423505.6	TSL:2	c.1214A>C	p.His405Pro	missense	Exon 12 of 12	ENSP00000406473.2
	PDHA1	ENST00000417819.6	TSL:3	c.1184A>C	p.His395Pro	missense	Exon 12 of 12	ENSP00000404616.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.4	N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.78	P
Vest4		0.77
MutPred		0.62		Gain of disorder (P = 0.0446)
MVP		0.90
MPC		0.20
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.95
gMVP		0.93
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1131691584; hg19: chrX-19377698;