NM_000284.4:c.861_862insT

Variant names:

• chrX-19357681-C-CT
• rs606231190
• NM_000284.4:c.861_862insT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000284.4(PDHA1):​c.861_862insT​(p.Arg288SerfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: PDHA1 NM_000284.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.55
• Publications: 2 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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-19357681-C-CT is Pathogenic according to our data. Variant chrX-19357681-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 10886.Status of the report is no_assertion_criteria_provided, 0 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.861_862insT	p.Arg288SerfsTer9	frameshift	Exon 9 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.975_976insT	p.Arg326SerfsTer9	frameshift	Exon 10 of 12	NP_001166925.1	P08559-4
	PDHA1	NM_001173455.2		c.882_883insT	p.Arg295SerfsTer9	frameshift	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.861_862insT	p.Arg288SerfsTer9	frameshift	Exon 9 of 11	ENSP00000394382.2	P08559-1
	PDHA1	ENST00000947567.1		c.1059_1060insT	p.Arg354SerfsTer9	frameshift	Exon 11 of 13	ENSP00000617626.1
	PDHA1	ENST00000947577.1		c.1020_1021insT	p.Arg341SerfsTer9	frameshift	Exon 10 of 12	ENSP00000617636.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	Pyruvate dehydrogenase E1-alpha deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=0/200	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: rs606231190; hg19: chrX-19375799;