rs606231189

Variant names:

• chrX-19359619-C-CCAAT
• rs606231189
• NM_000284.4:c.1142_1145dupATCA

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PS2 PVS1_Moderate PP4

This summary comes from the ClinGen Evidence Repository: The c.1142_c.1145dup variant in the PDHA1 gene is a frameshift variant in the final exon of PDHA1, which is predicted to escape nonsense mediated decay and result in amino acid truncation that removes less than 10% of the predicted protein product (PVS1_moderate PMID:30192042). This variant is absent from population databases (PM2). This variant has been reported in several patients with presentations consistent with PDHA1-related disease in the literature. While this variant has been reported several times before, only five cases met criteria for scoring, including four assumed de novo cases in PMID:10679936 and PMID:20002461, and one maternity confirmed de novo case in PMID:26865159. Several commercial testing laboratories (GeneDx, Illumina, and Ambry) have identified this variant was harbored by maternity confirmed de novo probands with presentations consistent with PDHA1-related disease (minimum of 3 and maximum of 6 probands- SCV001251622.1, SCV000252046.3, SCV000742395.2). Upon further review, the expert panel determined that while unable to confirm the identity of these patients, taken together these data in conjunction with the cases reported in the literature were sufficient to support elevating scoring to PS2_Very Strong per SVI de novo variant scoring criteria v1.0. PMID:1779625 and PMID:8504309 reported elevated pyruvate in the blood, and blood and CSF of the respective probands. PMID:23021068 performed PDC activity assays < 3rd percentile in fibroblasts (PP4). In summary, this variant meets criteria to be classified as a pathogenic of PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PVS1_moderate, PM2, PS2_Very Strong, PP4). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/18/2021. LINK:https://erepo.genome.network/evrepo/ui/classification/CA121215/MONDO:0019169/014

• Frequency: Genomes: not found (cov: 22)
• Consequence: PDHA1 NM_000284.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: -0.539
• Publications: 4 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

Specifications for PDHA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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.1142_1145dupATCA	p.Trp383SerfsTer6	frameshift	Exon 11 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.1256_1259dupATCA	p.Trp421SerfsTer6	frameshift	Exon 12 of 12	NP_001166925.1	P08559-4
	PDHA1	NM_001173455.2		c.1163_1166dupATCA	p.Trp390SerfsTer6	frameshift	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.1142_1145dupATCA	p.Trp383SerfsTer6	frameshift	Exon 11 of 11	ENSP00000394382.2	P08559-1
	PDHA1	ENST00000947567.1		c.1340_1343dupATCA	p.Trp449SerfsTer6	frameshift	Exon 13 of 13	ENSP00000617626.1
	PDHA1	ENST00000947577.1		c.1301_1304dupATCA	p.Trp436SerfsTer6	frameshift	Exon 12 of 12	ENSP00000617636.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Pyruvate dehydrogenase E1-alpha deficiency (8)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Pyruvate dehydrogenase complex deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.54
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs606231189; hg19: chrX-19377737;