ECHS1

protein-coding

enoyl-CoA hydratase, short chain 1, the group of MicroRNA protein coding host genes

Gene summary

The protein encoded by this gene functions in the second step of the mitochondrial fatty acid beta-oxidation pathway. It catalyzes the hydration of 2-trans-enoyl-coenzyme A (CoA) intermediates to L-3-hydroxyacyl-CoAs. The gene product is a member of the hydratase/isomerase superfamily. It localizes to the mitochondrial matrix. Transcript variants utilizing alternative transcription initiation sites have been described in the literature. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004092.4

Inheritance

ClinVar variants

P:84U:114B:86

Top phenotype

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr10:133,362,485-133,373,354

External References & Databases

Ensembl (ENSG00000127884)

Transcript & Mutation Effects

hg38 • Region Span ~10.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial short-chain Enoyl-Coa hydratase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014563

Submitter: Genomics England PanelApp

Leigh syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between ECHS1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of September 9, 2019. The ECHS1 gene encodes the mitochondrial short-chain enoyl-CoA hydratase (SCEH), which functions in the beta-oxidation of short chain fats, the isoleucine catabolic pathway, and the valine catabolic pathway. In the valine catabolic pathway, SCEH acts upstream of HIBCH and converts methacrylyl-CoA to (S)-3-hydroxyisobutyryl-CoA and acryloyl-CoA to 3-hydroxypropionyl-CoA. The exact disease mechanism has not been fully elucidated, but elevated levels of the SCEH substrate methacrylyl-CoA are toxic and impair functioning of the pyruvate dehydrogenase complex and the oxidative phosphorylation complexes (PMID: 25125611). The ECHS1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2014 (PMID 25125611). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 16 variants in 12 cases from 7 publications (PMIDs: 26000322, 25393721, 25125611, 28409271, 29575569, 28755360, 26099313). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression, functional alterations in patient cells, and rescue experiments (PMIDs: 27977873, 25613900, 26251176, 25125611, 26000322). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 9, 2019 (SOP Version 7).

mitochondrial short-chain Enoyl-Coa hydratase 1 deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014563

Submitter: Ambry Genetics

mitochondrial short-chain Enoyl-Coa hydratase 1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014563

Submitter: G2P

mitochondrial short-chain Enoyl-Coa hydratase 1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014563

Submitter: ClinGen

mitochondrial short-chain Enoyl-Coa hydratase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014563

Submitter: Ambry Genetics

mitochondrial short-chain Enoyl-Coa hydratase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014563

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial short-chain Enoyl-Coa hydratase 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014563

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiencyAR

Manifestation: Biochemical; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25125611; 25393721; 26251176; 29575569

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ECHS1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 309

Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiencyTotal: 86

Inborn genetic diseasesTotal: 34

not specifiedTotal: 26

ECHS1-related disorderTotal: 20

ECHS1-related disordersTotal: 16

Leigh syndromeTotal: 3

See casesTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004092.4. 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		1 clinvar	5 clinvar	80 clinvar	1 clinvar	87
missense	10 clinvar	45 clinvar	99 clinvar	5 clinvar		159
nonsense	2 clinvar	2 clinvar	1 clinvar			5
start loss	3 clinvar	2 clinvar				5
frameshift	7 clinvar	7 clinvar	2 clinvar			16
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	7 clinvar			12
Total	24	60	114	85	1	284

Highest pathogenic variant AF is 0.00017585876

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004092.4	RefSeq	NP_004083.3	8	MANE Select
ENST00000368547.4	Ensembl	ENSP00000357535.3	8	MANE Select
ENST00000857564.1	Ensembl	ENSP00000527623.1	9	Standard
ENST00000857564.2	Ensembl	ENSP00000527623.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tryptophan metabolism - Homo sapiens (human)
Butanoate metabolism - Homo sapiens (human)
beta-Alanine metabolism - Homo sapiens (human)
Lysine degradation - Homo sapiens (human)
Propanoate metabolism - Homo sapiens (human)

Biological Process

fatty acid beta-oxidation

Molecular Function

enoyl-CoA hydratase activity
protein binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000368547
Coding exons: 8
Length: 11210
Individuals with no LoFs: 125682
Homozygous LoFs: 0
Heterozygous LoFs: 59
Defined: 125741
p: 0.000235

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.863	131	162	0.809	0.00000908	1867
Missense (PolyPhen)		41	74.02	0.55391		823
Synonymous	-0.419	70	65.7	1.07	0.00000429	536
Loss of Function	1.69	7	13.8	0.509	6.78e-7	172

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.00030	0.00029	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Straight-chain enoyl-CoA thioesters from C4 up to at least C16 are processed, although with decreasing catalytic rate. Has high substrate specificity for crotonyl-CoA and moderate specificity for acryloyl-CoA, 3-methylcrotonyl-CoA and methacrylyl-CoA. It is noteworthy that binds tiglyl-CoA, but hydrates only a small amount of this substrate. {ECO:0000269|PubMed:26251176}.;

Intolerance Scores

LoFtool: 0.498
RVIS EVS: -0.07
RVIS percentile EVS: 48.35

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

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