Evidence Repository - Clinical Genome Resources

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

Link to SEPIO compliant JSON-LD document

Variant: NM_000284.4(PDHA1):c.844A>C (p.Met282Leu)

CA121220

10885 (ClinVar)

Gene: PDHA1

Condition: pyruvate dehydrogenase deficiency

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 9b20eee9-ea40-4e89-b0d2-b35d745e803a

HGVS expressions

NM_000284.4:c.844A>C

NM_000284.4(PDHA1):c.844A>C (p.Met282Leu)

ENST00000422285.7:c.844A>C

ENST00000379804.1:c.1A>C

ENST00000379806.9:c.958A>C

ENST00000422285.6:c.844A>C

ENST00000478795.1:n.283A>C

ENST00000481733.1:n.272A>C

ENST00000540249.5:c.751A>C

ENST00000545074.5:c.865A>C

NM_000284.3:c.844A>C

NM_001173454.1:c.958A>C

NM_001173455.1:c.865A>C

NM_001173456.1:c.751A>C

NM_001173454.2:c.958A>C

NM_001173455.2:c.865A>C

NM_001173456.2:c.751A>C

NC_000023.11:g.19357664A>C

CM000685.2:g.19357664A>C

NC_000023.10:g.19375782A>C

CM000685.1:g.19375782A>C

NC_000023.9:g.19285703A>C

NG_016781.1:g.18772A>C

Benign

BA1 BS2

BP4 PP3 PM1 PM5 PM2

Evidence Links 0

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The allele frequency of the c.844A>C; p. M282L variant in the PDHA1 gene is 0.207% in gnomAD, including 1,436 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 (>0.092%; gnomAD >16 hemizygotes). 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: (BA1, BS2). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 2/16/2021.

BA1

gnomAD allele frequency of 0.02072 which is > threshold of 0.00092 (PDHA1 VCEP established threshold), including 26% in East Asians. It is present in 1,436 hemizygotes.

BS2

It is present in 1,436 hemizygotes in gnomAD. PDHA1 VCEP established criteria for BS2 is > or equal to 16 hemizgytoes in gnomAD.

BP4

REVEL score 0.588

PP3

REVEL score 0.588

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

PM5

This variant is not novel as it is reported in gnomad at an allele frequency of 0.02072 including 1436 hemizygotes

PM2

This variant is present at allele frequency of 0.02072 in gnomAD

Approved on: 2021-04-02

Published on: 2021-05-06

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