Variant: NM_000284.4(PDHA1):c.839T>G (p.Ile280Ser)

CA412395150

655703 (ClinVar)

Gene: PDHA1

Condition: pyruvate dehydrogenase deficiency

Inheritance Mode: X-linked inheritance

UUID: b9bde7c4-6fe2-4b39-b2df-05689181e6be

HGVS expressions

NM_000284.4:c.839T>G
NM_000284.4(PDHA1):c.839T>G (p.Ile280Ser)
ENST00000422285.7:c.839T>G
ENST00000379804.1:c.-5T>G
ENST00000379806.9:c.953T>G
ENST00000422285.6:c.839T>G
ENST00000478795.1:n.278T>G
ENST00000481733.1:n.267T>G
ENST00000540249.5:c.746T>G
ENST00000545074.5:c.860T>G
NM_000284.3:c.839T>G
NM_001173454.1:c.953T>G
NM_001173455.1:c.860T>G
NM_001173456.1:c.746T>G
NM_001173454.2:c.953T>G
NM_001173455.2:c.860T>G
NM_001173456.2:c.746T>G
NC_000023.11:g.19357659T>G
CM000685.2:g.19357659T>G
NC_000023.10:g.19375777T>G
CM000685.1:g.19375777T>G
NC_000023.9:g.19285698T>G
NG_016781.1:g.18767T>G

Uncertain Significance

• Met criteria codes: PP3 PM2

• Not Met criteria codes: PS2 PP4 PM6 PM1 BA1 BS2 BS1 BP4

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The c.839T>G; p.I280S variant in the PDHA1 gene is a novel missense mutation that has not been reported in population databases (PM2). One patient with an episodic gait disorder, speech delay, cognitive delay, elevated serum and CSF lactate and brain MRI findings consistent with Leigh syndrome has been reported in the literature with this variant (PMID: 20691944). This variant was also seen in his reportedly unaffected mother and two uncles with dystonia, which was insufficient to meet criteria of 4 or more segregations for PP1 per ClinGen SVI. Serum pyruvate levels were normal for this patient and no other biochemical studies were performed. In silico meta-predictors indicate a deleterious effect (PP3). In summary, this variant meets criteria to be classified as a variant of uncertain significance of PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (PM2, PP3). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 2/16/2021.

Met criteria codes

• PP3: Predicted deleterious (REVEL score 0.931)
• PM2: Absent, gnomad queried 2/15/2021

Not Met criteria codes

• PS2: No de novo cases reported to date
• PP4: Pyruvate was normal in Egel et al 2010, no functional PDH activity assays were conducted
• PM6: No de novo cases reported to date
• PM1: See ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA- publication date April 30, 2020
• BA1: Absent, gnomAD queried 2/15/2021
• BS2: Not observed in gnomAD at all, no adult healthy males reported to date
• BS1: Absent, gnomAD queried 2/15/2021
• BP4: Revel Score 0.931

Approved on: 2021-04-02

Published on: 2021-05-06