Variant: NM_000284.4(PDHA1):c.999A>C (p.Glu333Asp)

CA10363173

378343 (ClinVar)

Gene: PDHA1

Condition: pyruvate dehydrogenase deficiency

Inheritance Mode: X-linked inheritance

UUID: b000cfe0-fa2b-4a64-89d9-917fee0b821c

HGVS expressions

NM_000284.4:c.999A>C
NM_000284.4(PDHA1):c.999A>C (p.Glu333Asp)
ENST00000422285.7:c.999A>C
ENST00000379804.1:c.156A>C
ENST00000379806.9:c.1113A>C
ENST00000422285.6:c.999A>C
ENST00000478795.1:n.438A>C
ENST00000481733.1:n.427A>C
ENST00000540249.5:c.906A>C
ENST00000545074.5:c.1020A>C
NM_000284.3:c.999A>C
NM_001173454.1:c.1113A>C
NM_001173455.1:c.1020A>C
NM_001173456.1:c.906A>C
NM_001173454.2:c.1113A>C
NM_001173455.2:c.1020A>C
NM_001173456.2:c.906A>C
NC_000023.11:g.19359015A>C
CM000685.2:g.19359015A>C
NC_000023.10:g.19377133A>C
CM000685.1:g.19377133A>C
NC_000023.9:g.19287054A>C
NG_016781.1:g.20123A>C
NG_021184.1:g.161247T>G

Benign

• Met criteria codes: BS1 BS2

• Not Met criteria codes: BP4 PVS1 PS1 BA1 PP3 PM5 PM1 PM2

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The allele frequency of the c.999A>C variant in the PDHA1 gene is 0.044% in gnomAD, including 25 hemizygotes. This allele frequency, and the frequency with which it is seen in hemizygotes in the general population are high enough to be classified as benign based on thresholds defined by the ClinGen PDHA1 Variant Curation Expert Panel (>0.0092%- BS1; gnomAD >16 hemizygotes- BS2). In silico predictors provide a conflicting score (REVEL score 0.509). In summary, this variant meets criteria to be classified as benign for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (BS1, BS2). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/6/2021.

Met criteria codes

• BS1: 0.044% in gnomAD (AF is 0.0004393); BS1 strong criteria for PDHA1 is >0.0092%
• BS2: present in 25 hemizygotes in gnomAD 4/5/2021

Not Met criteria codes

• BP4: Conflicting REVEL score 0.509
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No other nucleotide changes leading to this amino acid change reported
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: Conflicting REVEL score 0.509
• PM5: No other changes at this residue
• PM1: Not in these domains
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2021-05-06

Published on: 2021-05-06