ECE1

Chr 1ADMulti

endothelin converting enzyme 1

Also known as: ECE

NCBI Gene: 1889 ENSG00000117298 UniProt: P42892 OMIM: 600423

The protein converts big endothelin-1 to endothelin-1, a vasoactive peptide important for vascular tone and development. Mutations cause Hirschsprung disease with cardiac defects and autonomic dysfunction, with autosomal dominant inheritance. This gene is highly constrained against loss-of-function variation (pLI 0.96), reflecting its critical role in cardiovascular and enteric nervous system development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is involved in proteolytic processing of endothelin precursors to biologically active peptides. Mutations in this gene are associated with Hirschsprung disease, cardiac defects and autonomic dysfunction. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Sep 2009]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/MultiLOEUF 0.322 OMIM phenotypes

Clinical Summary— ECE1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.960

Z-score 4.91

OE 0.17 (0.10–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.31Z-score

OE missense 0.70 (0.63–0.76)

315 obs / 453.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.17 (0.10–0.32)

0≤0.351.4

Missense OE?0.70 (0.63–0.76)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 7 / 40.9Missense obs/exp: 315 / 453.2Syn Z: 0.09

This gene — mechanism propensity

0.4189th %ile

GOF

0.5759th %ile

LOF

0.4726th %ile

The Badonyi & Marsh model scores gain-of-function highest, but genomic evidence most strongly supports loss-of-function (haploinsufficiency) as the primary mechanism.

LOF1 literature citation · LOEUF 0.32

Literature Evidence

LOFA loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction1

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

References