dbSNP rs606231188: PDHA1:p.Glu305_Glu306insAspSerTyrArgThrArgGlu (chrX-19358911-C-CATAGTTACCGTACACGAGAAG) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM4PP5

The NM_000284.4(PDHA1):c.900-3_917dupTAGTTACCGTACACGAGAAGA(p.Glu305_Glu306insAspSerTyrArgThrArgGlu) 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 23)

Consequence

PDHA1
NM_000284.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -3.78

Publications

0 publications found

Variant links:

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, Orphanet, G2P, Ambry Genetics
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PDHA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000284.4

PM4

Nonframeshift variant in NON repetitive region in NM_000284.4.

PP5

Variant X-19358911-C-CATAGTTACCGTACACGAGAAG is Pathogenic according to our data. Variant chrX-19358911-C-CATAGTTACCGTACACGAGAAG is described in ClinVar as Pathogenic. ClinVar VariationId is 10877.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDHA1	NM_000284.4	MANE Select	c.900-3_917dupTAGTTACCGTACACGAGAAGA	p.Glu305_Glu306insAspSerTyrArgThrArgGlu	disruptive_inframe_insertion	Exon 10 of 11	NP_000275.1	P08559-1
PDHA1	NM_001173454.2		c.1014-3_1031dupTAGTTACCGTACACGAGAAGA	p.Glu343_Glu344insAspSerTyrArgThrArgGlu	disruptive_inframe_insertion	Exon 11 of 12	NP_001166925.1	P08559-4
PDHA1	NM_001173455.2		c.921-3_938dupTAGTTACCGTACACGAGAAGA	p.Glu312_Glu313insAspSerTyrArgThrArgGlu	disruptive_inframe_insertion	Exon 10 of 11	NP_001166926.1	P08559-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.900-5_900-4insATAGTTACCGTACACGAGAAG	splice_region intron	N/A	ENSP00000394382.2	P08559-1
PDHA1	ENST00000947567.1		c.1098-5_1098-4insATAGTTACCGTACACGAGAAG	splice_region intron	N/A	ENSP00000617626.1
PDHA1	ENST00000947577.1		c.1059-5_1059-4insATAGTTACCGTACACGAGAAG	splice_region intron	N/A	ENSP00000617636.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pyruvate dehydrogenase E1-alpha deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-3.8

Mutation Taster

=100/0

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over