ETHE1

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

Basic information

Region (hg38): 19:43506719-43527230

Links

ENSG00000105755 ∙ NCBI:23474 ∙ OMIM:608451 ∙ HGNC:23287 ∙ Uniprot:O95571 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• ethylmalonic encephalopathy (Definitive), mode of inheritance: AR
• ethylmalonic encephalopathy (Strong), mode of inheritance: AR
• ethylmalonic encephalopathy (Supportive), mode of inheritance: AR
• Leigh syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ethylmalonic encephalopathy	AR	Biochemical	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	Biochemical; Cardiovascular; Gastrointestinal; Neurologic	14732903; 18593870; 20528888; 20657580; 20978941; 21472225; 22584649; 22805253

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ETHE1 gene.

• Ethylmalonic encephalopathy (34 variants)
• not provided (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ETHE1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	124	2	129
missense	4	9	55	4	1	73
nonsense	6	4	1			11
start loss	3					3
frameshift	20	10				30
inframe indel			1			1
splice donor/acceptor (+/-2bp)	2	15				17
splice region		1	4	27	1	33
non coding			3	58	18	79
Total	35	38	63	186	21

Highest pathogenic variant AF is 0.0000263

Variants in ETHE1

This is a list of pathogenic ClinVar variants found in the ETHE1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
19-43506758-T-G		Ethylmalonic encephalopathy	Uncertain significance (Jan 12, 2018)
19-43506795-C-A		Ethylmalonic encephalopathy	Benign (Aug 18, 2020)
19-43506802-C-T		Ethylmalonic encephalopathy	Uncertain significance (Jan 13, 2018)
19-43506819-T-C		Ethylmalonic encephalopathy	Uncertain significance (Jan 13, 2018)
19-43506853-G-A		Ethylmalonic encephalopathy	Likely benign (Jun 11, 2022)
19-43506853-G-T		Ethylmalonic encephalopathy	Likely benign (Sep 10, 2023)
19-43506854-G-A		Ethylmalonic encephalopathy	Uncertain significance (Aug 18, 2020)
19-43506855-C-T		not specified	Uncertain significance (Oct 17, 2023)
19-43506856-A-C		Ethylmalonic encephalopathy	Likely benign (Jan 24, 2024)
19-43506856-A-G		Ethylmalonic encephalopathy	Likely benign (Oct 22, 2021)
19-43506858-T-C		Ethylmalonic encephalopathy	Uncertain significance (Feb 03, 2022)
19-43506859-G-A		Ethylmalonic encephalopathy	Likely benign (Aug 29, 2023)
19-43506868-C-T		Ethylmalonic encephalopathy	Likely benign (Aug 06, 2022)
19-43506873-C-T			Likely pathogenic (Jul 01, 2020)
19-43506874-A-G		Ethylmalonic encephalopathy	Likely benign (Mar 10, 2023)
19-43506878-C-T		Inborn genetic diseases	Uncertain significance (May 24, 2023)
19-43506881-A-C		Ethylmalonic encephalopathy	Uncertain significance (Dec 28, 2023)
19-43506883-G-A		Ethylmalonic encephalopathy	Likely benign (Feb 04, 2022)
19-43506890-G-A		Ethylmalonic encephalopathy	Uncertain significance (Aug 21, 2022)
19-43506897-CA-C		Ethylmalonic encephalopathy	Likely pathogenic (-)
19-43506909-G-A		Ethylmalonic encephalopathy	Likely benign (Jan 05, 2024)
19-43506910-G-C		Ethylmalonic encephalopathy	Likely benign (Feb 21, 2023)
19-43507745-C-T			Benign (Aug 06, 2019)
19-43507763-T-C		Ethylmalonic encephalopathy	Benign (May 07, 2021)
19-43507763-TAGACCCAGGAGTCCAGGCCCCCAGCCTCTCCTCCCTC-T			Benign (Jun 26, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ETHE1	protein_coding	protein_coding	ENST00000292147	7	20526

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000460	0.415	125727	0	20	125747	0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.957	110	142	0.774	0.00000762	1621
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000179	0.000179
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.000107	0.000105
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.000163	0.000163

dbNSFP

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}.
• Pathway: Sulfur metabolism - Homo sapiens (human);Sulfide oxidation to sulfate;Degradation of cysteine and homocysteine;Metabolism of amino acids and derivatives;Metabolism;Sulfur amino acid metabolism (Consensus)

Recessive Scores

• pRec: 0.166

Intolerance Scores

• loftool: 0.329
• rvis_EVS: -0.32
• rvis_percentile_EVS: 31.46

Haploinsufficiency Scores

• pHI: 0.0879
• hipred: Y
• hipred_score: 0.600
• ghis: 0.458

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.752

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ethe1
• Phenotype: homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); growth/size/body region phenotype; renal/urinary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: glutathione metabolic process;sulfide oxidation, using sulfide:quinone oxidoreductase;hydrogen sulfide metabolic process
• Cellular component: nucleoplasm;cytoplasm;mitochondrion;mitochondrial matrix
• Molecular function: iron ion binding;hydrolase activity, acting on ester bonds;sulfur dioxygenase activity