ETHE1

Chr 19AR

ETHE1 persulfide dioxygenase

Also known as: HSCO, YF13H12

NCBI Gene: 23474 ENSG00000105755 UniProt: O95571 OMIM: 608451

The ETHE1 protein is a sulfur dioxygenase that catalyzes the oxidation of persulfide substrates in the mitochondrial sulfide oxidation pathway, preventing toxic accumulation of hydrogen sulfide that can inhibit cytochrome c oxidase. Mutations cause ethylmalonic encephalopathy, an infantile-onset metabolic disorder affecting the brain, gastrointestinal tract, and peripheral vessels with autosomal recessive inheritance. This gene shows relatively low constraint against loss-of-function variants (pLI near zero, LOEUF 1.46).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the metallo beta-lactamase family of iron-containing proteins involved in the mitochondrial sulfide oxidation pathway. The encoded protein catalyzes the oxidation of a persulfide substrate to sulfite. Certain mutations in this gene cause ethylmalonic encephalopathy, an infantile metabolic disorder affecting the brain, gastrointestinal tract and peripheral vessels. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.461 OMIM phenotype

VCEP Guidelines: Mitochondrial DiseaseReleased

View Specifications ClinGen Panel

Clinical Summary— ETHE1

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

108 unique Pathogenic / Likely Pathogenic· 96 VUS of 487 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ETHE1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.46LOEUF

pLI 0.000

Z-score 0.49

OE 0.84 (0.50–1.46)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.96Z-score

OE missense 0.77 (0.66–0.91)

110 obs / 142.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.84 (0.50–1.46)

0≤0.351.4

Missense OE?0.77 (0.66–0.91)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 9 / 10.7Missense obs/exp: 110 / 142.1Syn Z: 0.45

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveETHE1-related ethylmalonic encephalopathyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6744th %ile

GOF

0.5857th %ile

LOF

0.4331th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

487 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43

Likely Pathogenic65

VUS96

Likely Benign229

Benign26

Conflicting11

Pathogenic

Likely Pathogenic

VUS

229

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	29	7	7	0	43
Likely Pathogenic	47	13	5	0	65
VUS	1	77	13	5	96
Likely Benign	1	2	94	132	229
Benign	0	1	22	3	26
Conflicting	—				11
Total	78	100	141	140	470

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

7 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap ETHE1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →