NM_000284.4:c.1050_1133dupCCAGTTTGCCACGGCCGATCCTGAGCCACCTTTGGAAGAGCTGGGCTACCACATCTACTCCAGCGACCCACCTTTTGAAGTTCG

Variant names:

• chrX-19359529-C-CCCAGTTTGCCACGGCCGATCCTGAGCCACCTTTGGAAGAGCTGGGCTACCACATCTACTCCAGCGACCCACCTTTTGAAGTTCG
• rs1555935486
• NM_000284.4:c.1050_1133dupCCAGTTTGCCACGGCCGATCCTGAGCCACCTTTGGAAGAGCTGGGCTACCACATCTACTCCAGCGACCCACCTTTTGAAGTTCG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4 PP5_Moderate

The NM_000284.4(PDHA1):​c.1050_1133dupCCAGTTTGCCACGGCCGATCCTGAGCCACCTTTGGAAGAGCTGGGCTACCACATCTACTCCAGCGACCCACCTTTTGAAGTTCG​(p.Arg378_Gly379insGlnPheAlaThrAlaAspProGluProProLeuGluGluLeuGlyTyrHisIleTyrSerSerAspProProPheGluValArg) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PDHA1 NM_000284.4 disruptive_inframe_insertion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.0580
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000284.4.
• PP5: Variant X-19359529-C-CCCAGTTTGCCACGGCCGATCCTGAGCCACCTTTGGAAGAGCTGGGCTACCACATCTACTCCAGCGACCCACCTTTTGAAGTTCG is Pathogenic according to our data. Variant chrX-19359529-C-CCCAGTTTGCCACGGCCGATCCTGAGCCACCTTTGGAAGAGCTGGGCTACCACATCTACTCCAGCGACCCACCTTTTGAAGTTCG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 495793.Status of the report is criteria_provided_single_submitter, 1 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.1050_1133dupCCAGTTTGCCACGGCCGATCCTGAGCCACCTTTGGAAGAGCTGGGCTACCACATCTACTCCAGCGACCCACCTTTTGAAGTTCG	p.Arg378_Gly379insGlnPheAlaThrAlaAspProGluProProLeuGluGluLeuGlyTyrHisIleTyrSerSerAspProProPheGluValArg	disruptive_inframe_insertion	Exon 11 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.1164_1247dupCCAGTTTGCCACGGCCGATCCTGAGCCACCTTTGGAAGAGCTGGGCTACCACATCTACTCCAGCGACCCACCTTTTGAAGTTCG	p.Arg416_Gly417insGlnPheAlaThrAlaAspProGluProProLeuGluGluLeuGlyTyrHisIleTyrSerSerAspProProPheGluValArg	disruptive_inframe_insertion	Exon 12 of 12	NP_001166925.1	P08559-4
	PDHA1	NM_001173455.2		c.1071_1154dupCCAGTTTGCCACGGCCGATCCTGAGCCACCTTTGGAAGAGCTGGGCTACCACATCTACTCCAGCGACCCACCTTTTGAAGTTCG	p.Arg385_Gly386insGlnPheAlaThrAlaAspProGluProProLeuGluGluLeuGlyTyrHisIleTyrSerSerAspProProPheGluValArg	disruptive_inframe_insertion	Exon 11 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.1050_1133dupCCAGTTTGCCACGGCCGATCCTGAGCCACCTTTGGAAGAGCTGGGCTACCACATCTACTCCAGCGACCCACCTTTTGAAGTTCG	p.Arg378_Gly379insGlnPheAlaThrAlaAspProGluProProLeuGluGluLeuGlyTyrHisIleTyrSerSerAspProProPheGluValArg	disruptive_inframe_insertion	Exon 11 of 11	ENSP00000394382.2	P08559-1
	PDHA1	ENST00000947567.1		c.1248_1331dupCCAGTTTGCCACGGCCGATCCTGAGCCACCTTTGGAAGAGCTGGGCTACCACATCTACTCCAGCGACCCACCTTTTGAAGTTCG	p.Arg444_Gly445insGlnPheAlaThrAlaAspProGluProProLeuGluGluLeuGlyTyrHisIleTyrSerSerAspProProPheGluValArg	disruptive_inframe_insertion	Exon 13 of 13	ENSP00000617626.1
	PDHA1	ENST00000947577.1		c.1209_1292dupCCAGTTTGCCACGGCCGATCCTGAGCCACCTTTGGAAGAGCTGGGCTACCACATCTACTCCAGCGACCCACCTTTTGAAGTTCG	p.Arg431_Gly432insGlnPheAlaThrAlaAspProGluProProLeuGluGluLeuGlyTyrHisIleTyrSerSerAspProProPheGluValArg	disruptive_inframe_insertion	Exon 12 of 12	ENSP00000617636.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Pyruvate dehydrogenase complex deficiency (1)
1	-	-	Pyruvate dehydrogenase E1-alpha deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.058
Mutation Taster		=40/60	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555935486; hg19: chrX-19377647;