rs606231185

chrX-19358940-GGAAGTAA-GchrX-19358940-GGAAGTAA-GGAAGTAAGAAGTAA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000284.4(PDHA1):c.934_940del(p.Ser312ValfsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E309E) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PDHA1 NM_000284.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.51

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-19358940-GGAAGTAA-G is Pathogenic according to our data. Variant chrX-19358940-GGAAGTAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 10872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.934_940del	p.Ser312ValfsTer12	frameshift_variant	10/11	ENST00000422285.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHA1	ENST00000422285.7	c.934_940del	p.Ser312ValfsTer12	frameshift_variant	10/11	1	NM_000284.4	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1077367 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 345273

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000010872, PMID:2378353). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 12, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 10, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PDHA1 protein in which other variant(s) (p.Glu358Glyfs*12) have been determined to be pathogenic (PMID: 1907799). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 10872). This variant is also known as 7-bp deletion at nucleotide 1032, 7-bp deletion at bp 927. This premature translational stop signal has been observed in individual(s) with pyruvate dehydrogenase deficiency (PMID: 2378353, 8504306, 27144126). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser312Valfs*12) in the PDHA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the PDHA1 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Pyruvate dehydrogenase E1-alpha deficiency (MIM#312170). (I) 0110 - This gene is associated with X-linked dominant disease. Affected males have also been reported with variants resulting in partial enzyme deficiency, however severe variants are presumed to be embryonically lethal (PMID: 22142326). (I) 0115 - Variants in this gene are known to have variable expressivity. Depending on the residual enzymatic activity resulting from the PDHA1 variant, the severity of phenotypic presentation can vary. Additionally, the severity in females is dependent on X-chromosome inactivation patterns (OMIM, PMID: 22142326). (I) 0201 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction with less than 1/3 of the protein sequence affected). However functional studies have shown that this variant causes a 30% reduction in detectable PDHA1 protein with no truncated protein observed and has therefore been shown to cause nonsense-mediated decay (PMID: 2378353). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is predicted to truncate the annotated pyruvate dehydrogenase E1 component domain (DECIPHER). (I) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over five individuals with pyruvate dehydrogenase E1-alpha deficiency (ClinVar, PMIDs: 2378353, 7887409, 25356417, 27144126). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001- This variant has strong functional evidence supporting abnormal protein function. Functional studies in patient cells showed 22% of residual enzyme activity compared to WT (PMID: 25356417). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 27, 2022	The PDHA1 c.934_940del variant is classified as Pathogenic (PVS1_Strong, PS4, PM2) This PDHA1 c.934_940del variant is located in exon 10/11 and is predicted to cause a shift in the reading frame at codon 312 with a termination of the protein 12 amino acids downstream. This is not expected to undergo nonsense-mediated decay however this variant disrupts the last 79 amino acids which are critical for protein function (PVS1_Strong). This variant has been reported in at least 15 probands with a clinical presentation consistent with pyruvate dehydrogenase E1-alpha deficiency and has been confirmed denovo in a number of families (PMID#30842224, 33768920, 34863613, 2378353, 8504306, 27144126) (PS4). The variant has been reported in dbSNP (rs606231185), is reported as disease causing in the HGMD database (CD900295) is reported as pathogenic by other diagnostic laboratories (ClinVar#10872) and is absent from population databases (PM2). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 03, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2022	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 79 amino acids are lost and replaced with 11 incorrect amino acids; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8962591, 2378353, 30842224, 25356417, 1301207, 8504306, 27144126, 1907799, 7887408, 33768920, 34863613) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231185; hg19: chrX-19377058;