ETHE1

protein-coding

ETHE1 persulfide dioxygenase, the group of MBL domain containing glyoxalase 2 subfamily

Gene summary

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]

MANE transcript

NM_014297.5

Inheritance

ClinVar variants

P:102U:93B:143

Top phenotype

Ethylmalonic encephalopathy

gnomAD constraint

pLI —, LoF o/e 0.84

Max pathogenic AF

—

Genomic locus

chr19:43,506,719-43,527,230

External References & Databases

Ensembl (ENSG00000105755)

Transcript & Mutation Effects

hg38 • Region Span ~20.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between ETHE1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 10, 2018. 34 articles were reviewed. ETHE1 was first reported in association with ethylmalonic encephalopathy in 2004 (Tiranti et al., PMID 14732903) and first associated Leigh syndrome spectrum in 2006 (Herberle et al., PMID 16376514). At least 39 unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting homozygous loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 7 probands with Leigh syndrome spectrum in 7 publications (PMID: 18593870, 20978941, 20528888, 27830356, 26917598, 16376514). This gene-disease association is supported by expression, animal model, and rescue experiments. As previously stated, this gene has been primarily associated with ethylmalonic encephalopathy (progressive disorder characterized by mutisystem involvement including chronic diarrhea, developmental delay, petechiae, and acrocyanosis). This phenotype will be assessed separately. In summary, there is definitive evidence to support the relationship between ETHE1 and autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association to reach a definitive classification. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 10, 2018 (SOP Version 6).

ethylmalonic encephalopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011229

Submitter: PanelApp Australia

ethylmalonic encephalopathySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011229

Submitter: Orphanet

ethylmalonic encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011229

Submitter: G2P

ethylmalonic encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011229

Submitter: Natera

ethylmalonic encephalopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011229

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Ethylmalonic encephalopathyAR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Neurologic

Intervention: Biochemical

Rationale: The condition can manifest with features including neurological impairment and chronic diarrhea, and dietary (eg, with restriction of branched amino acids, fatty acids, and methionine) and medical treatment (eg, with metronidazole and N-acetylcysteine) has been reported as having clinical benefit

Refs: 14732903; 18593870; 20528888; 20657580; 20978941; 21472225; 22584649; 22805253

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ETHE1 variants in ClinVar

8 Conditions Cataloged

Ethylmalonic encephalopathyTotal: 400

not providedTotal: 48

Inborn genetic diseasesTotal: 26

not specifiedTotal: 24

ETHE1-related disorderTotal: 7

ETHE1-related disordersTotal: 5

Abnormality of the nervous systemTotal: 1

Type 2 diabetes mellitusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014297.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	136 clinvar	2 clinvar	142
missense	4 clinvar	14 clinvar	81 clinvar	4 clinvar	1 clinvar	104
nonsense	6 clinvar	7 clinvar	1 clinvar			14
start loss	3 clinvar	2 clinvar				5
frameshift	20 clinvar	22 clinvar	1 clinvar			43
splice donor/acceptor (+/-2bp)	4 clinvar	20 clinvar	6 clinvar			30
Total	37	65	93	140	3	338

Highest pathogenic variant AF is 0.000024782319

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014297.5	RefSeq	NP_055112.2	7	MANE Select
ENST00000292147.7	Ensembl	ENSP00000292147.1	7	MANE Select
NM_001320867.2	RefSeq	NP_001307796.1	7	Standard
NM_001320868.2	RefSeq	NP_001307797.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Sulfur metabolism - Homo sapiens (human)
Sulfide oxidation to sulfate
Degradation of cysteine and homocysteine
Metabolism of amino acids and derivatives
Metabolism

Biological Process

glutathione metabolic process
sulfide oxidation, using sulfide:quinone oxidoreductase
hydrogen sulfide metabolic process

Molecular Function

iron ion binding
hydrolase activity, acting on ester bonds
sulfur dioxygenase activity

Cellular Component

nucleoplasm
cytoplasm
mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000292147
Coding exons: 7
Length: 20526
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125747
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.957	110	142	0.774	0.00000762	1621
Missense (PolyPhen)		29	52.969	0.54749		595
Synonymous	0.447	56	60.4	0.927	0.00000309	536
Loss of Function	0.490	9	10.7	0.839	4.72e-7	126

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Sulfur dioxygenase that plays an essential role in hydrogen sulfide catabolism in the mitochondrial matrix. Hydrogen sulfide (H(2)S) is first oxidized by SQRDL, giving rise to cysteine persulfide residues. ETHE1 consumes molecular oxygen to catalyze the oxidation of the persulfide, once it has been transferred to a thiophilic acceptor, such as glutathione (R-SSH). Plays an important role in metabolic homeostasis in mitochondria by metabolizing hydrogen sulfide and preventing the accumulation of supraphysiological H(2)S levels that have toxic effects, due to the inhibition of cytochrome c oxidase. First described as a protein that can shuttle between the nucleus and the cytoplasm and suppress p53-induced apoptosis by sequestering the transcription factor RELA/NFKB3 in the cytoplasm and preventing its accumulation in the nucleus (PubMed:12398897). {ECO:0000269|PubMed:12398897, ECO:0000269|PubMed:14732903, ECO:0000269|PubMed:19136963, ECO:0000269|PubMed:23144459}.;

Recessive Scores

pRec: 0.166

Intolerance Scores

LoFtool: 0.329
RVIS EVS: -0.32
RVIS percentile EVS: 31.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.752

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium