The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_000284.3(PDHA1):c.1132C>T (p.Arg378Cys)

CA323094

214936 (ClinVar)

Gene: PDHA1
Condition: pyruvate dehydrogenase deficiency
Inheritance Mode: X-linked inheritance
UUID: ce28d7f7-3561-4601-9603-7bb8aa198a9e
Approved on: 2021-10-25
Published on: 2021-10-25

HGVS expressions

NM_000284.3:c.1132C>T
NM_000284.3(PDHA1):c.1132C>T (p.Arg378Cys)
NC_000023.11:g.19359612C>T
CM000685.2:g.19359612C>T
NC_000023.10:g.19377730C>T
CM000685.1:g.19377730C>T
NC_000023.9:g.19287651C>T
NG_016781.1:g.20720C>T
NG_021184.1:g.160650G>A
ENST00000422285.7:c.1132C>T
ENST00000379804.1:c.289C>T
ENST00000379806.9:c.1246C>T
ENST00000422285.6:c.1132C>T
ENST00000478795.1:n.571C>T
ENST00000540249.5:c.1039C>T
ENST00000545074.5:c.1153C>T
NM_001173454.1:c.1246C>T
NM_001173455.1:c.1153C>T
NM_001173456.1:c.1039C>T
NM_000284.4:c.1132C>T
NM_001173454.2:c.1246C>T
NM_001173455.2:c.1153C>T
NM_001173456.2:c.1039C>T
NM_000284.4(PDHA1):c.1132C>T (p.Arg378Cys)
More

Pathogenic

Met criteria codes 5
PP4 PP3 PM2 PM5 PM6_Strong
Not Met criteria codes 7
PP1 PM4 PM1 BA1 PVS1 BS1 PS1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
The c.1132C>T (p.R378C) variant in PDHA1 has been reported in multiples males and females with pyruvate dehydrogenase deficiency and is one of the more common pathogenic variants seen in this cohort (PMID: 22896851). It has been seen in at least three individuals with decreased pyruvate dehydrogenase activity (PP4; Patient 6 in PMID: 8962591; Subject M-7 in PMID: 20002461; Subject 35-2 in PMID: 10679936). This variant has been identified as a de novo occurrence (unconfirmed parental relationships) in at least 4 unrelated individuals with pyruvate dehydrogenase deficiency [PM6_Strong; utilized ClinGen SVI de novo scoring guidance (phenotype consistent but not highly specific); PMID: 10679936, subject 35-2; PMID: 20002461, subject M-7; PMID: 21914562, subject AM8; PMID: 21914562, subject AF22]. Of note, to our knowledge, there are no reports of this variant being inherited from a healthy mother, however it is important to note that not all cases reported in the literature had mothers who were tested. This variant is absent from gnomAD v2.1.1 (PM2). Another missense variant at this position [c.1133G>A, p.R378H] has been reported in at least six other probands (PM5; PMIDs: 8032855 - 1 case, 7887409 - 2 cases, 9409363 - 3 cases) and is a known pathogenic variant. The computational predictor REVEL gives a score of 0.907, which is above the threshold of 0.75, evidence that correlates with impact to PDHA1 function (PP3). In summary, this variant meets criteria to be classified as pathogenic for pyruvate dehydrogenase deficiency inherited in an X-linked manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on May 20, 2020. PDHA1-specific ACMG/AMP criteria applied: PM2, PM5, PM6_strong, PP3, PP4.
Met criteria codes
PP4
At least three patients with this variant displayed decreased pyruvate dehydrogenase activity (PP4; Patient 6 in PMID: 8962591; Subject M-7 in PMID: 20002461; Subject 35-2 in PMID: 10679936).

PP3
The computational predictor REVEL gives a score of 0.907, which is above the threshold of 0.75, evidence that correlates with impact to PDHA1 function (PP3).
PM2
This variant is absent from gnomAD v2.1.1 (PM2).
PM5
Another missense variant [c.1133G>A, p.R378H] has been reported in at least six other probands (PMIDs: 8032855 - 1 case, 7887409 - 2 cases, 9409363 - 3 cases) and is a known pathogenic variant.
PM6_Strong
Utilized ClinGen SVI de novo scoring guidance (phenotype consistent but not highly specific); TOTAL 2 = 0.5 (PMID: 10679936, subject 35-2) + 0.5 (PMID: 20002461, subject M-7) + 0.5 (PMID: 21914562, subject AM8) + 0.5 (PMID: 21914562, subject AF22)
Not Met criteria codes
PP1
No large families reported to date
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Not located in domains outlined in specifications
BA1
Absent
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Absent
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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