Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000284.4(PDHA1):c.506C>T (p.Ala169Val)

CA323959

214941 (ClinVar)

Gene: PDHA1
Condition: pyruvate dehydrogenase deficiency
Inheritance Mode: X-linked inheritance
Link to MONDO
UUID: dc5261dd-3db5-4b9d-a01b-0c4006234082

HGVS expressions

NM_000284.4:c.506C>T
NM_000284.4(PDHA1):c.506C>T (p.Ala169Val)
ENST00000422285.7:c.506C>T
ENST00000355808.9:c.527C>T
ENST00000379805.3:c.506C>T
ENST00000379806.9:c.620C>T
ENST00000422285.6:c.506C>T
ENST00000479146.1:n.341C>T
ENST00000540249.5:c.506C>T
ENST00000545074.5:c.527C>T
NM_000284.3:c.506C>T
NM_001173454.1:c.620C>T
NM_001173455.1:c.527C>T
NM_001173456.1:c.506C>T
NM_001173454.2:c.620C>T
NM_001173455.2:c.527C>T
NM_001173456.2:c.506C>T
NC_000023.11:g.19353169C>T
CM000685.2:g.19353169C>T
NC_000023.10:g.19371287C>T
CM000685.1:g.19371287C>T
NC_000023.9:g.19281208C>T
NG_016781.1:g.14277C>T

Pathogenic

Met criteria codes 5
PM2 PM1 PS2 PP4 PP3
Not Met criteria codes 5
PM5 BA1 BS2 BS1 PS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
The c.506C>T variant in the PDHA1 gene is a missense mutation occurring in a hotspot domain (aa position A169, located in α β heterodimer interface (PM1). This variant is absent from population databases (PM2). This variant has been reported in three individuals in the literature with presentations consistent with PDHA1-related disease. These three cases include two assumed de novo cases (PMID: 20002461 and PMID: 21914562), and one maternity confirmed de novo case via exome sequencing in PMID: 31683770 (PS2). PMID: 20002461 Western Blot studies showed reduced E1a, and Imbard et al 2011 PDC studies indicate activity <3rd percentile in fibroblasts (PP4). In silico predictors suggest a deleterious effect (REVEL score – 0.946; PP3). 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: (PM1, PM2, PS2, PP3, PP4). This was reviewed with the PDHA1 expert panel on 4/6/2021 and approved on 4/6/2021.
Met criteria codes
PM2
Absent from gnomAD 4/3/2021
PM1
located in α β heterodimer interface
PS2
Utilized ClinGen SVI de novo scoring guidance (phenotype consistent but not highly specific); TOTAL = 2.0 = [0.5 (Patient M-1 in PMID: 20002461) + 0.5 (Patient AF15 in PMID: 21914562)+1.0 (Patient Pt20 in PMID: 31683770); exome sequencing performed to confirm maternity]
PP4
E1a activity decreased in Quintana et al 2010 on Western Blot. PDC activity <3rd percentile in Imbard et al 2011 in fibroblasts
PP3
Predicted deleterious (REVEL SCORE 0.946)
Not Met criteria codes
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
not seen in gnomAD, nor reported in mother's of reported patient's to date
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
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
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