HECW2

Chr 2AD

HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2

Also known as: NDHSAL, NEDL2

NCBI Gene: 57520 ENSG00000138411 UniProt: Q9P2P5 OMIM: 617245

The protein functions as an E3 ubiquitin ligase that regulates neural crest cell proliferation, migration and differentiation through GDNF/Ret signaling, and also stabilizes endothelial cell junctions via angiomotin-like 1 regulation. Loss-of-function mutations cause autosomal dominant neurodevelopmental disorder with hypotonia, seizures, and absent language. The protein is extremely intolerant to loss-of-function variants, indicating haploinsufficiency as the likely pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of a family of E3 ubiquitin ligases which plays an important role in the proliferation, migration and differentiation of neural crest cells as a regulator of glial cell line-derived neurotrophic factor (GDNF)/Ret signaling. This gene also plays an important role in angiogenesis through stabilization of endothelial cell-to-cell junctions as a regulator of angiomotin-like 1 stability. The encoded protein contains an N-terminal calcium/lipid-binding (C2) domain involved in membrane targeting, two-four WW domains responsible for cellular localization and substrate recognition, and a C-terminal homologous with E6-associated protein C-terminus (HECT) catalytic domain. Naturally occurring mutations in this gene are associated with neurodevelopmental delay, hypotonia, and epilepsy. The decreased expression of this gene in the aganglionic colon is associated with Hirschsprung's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.261 OMIM phenotype

Clinical Summary— HECW2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

39 unique Pathogenic / Likely Pathogenic· 315 VUS of 557 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.26LOEUF

pLI 1.000

Z-score 6.98

OE 0.16 (0.10–0.26)

Highly constrained

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

Missense Constraint?

3.31Z-score

OE missense 0.69 (0.65–0.74)

625 obs / 904.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.16 (0.10–0.26)

0≤0.351.4

Missense OE?0.69 (0.65–0.74)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 13 / 80.6Missense obs/exp: 625 / 904.8Syn Z: 0.78

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedHECW2-related neurodevelopmental disorder (biallelic)OTHERAR

definitiveHECW2-related neurodevelopmental disorder (monoallelic)OTHERAD

This gene — mechanism propensity

0.3694th %ile

GOF

0.4579th %ile

LOF

0.64top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.26

DN1 literature citation

Literature Evidence

DNThese findings suggest that the dominant negative effects of missense variants around the HECT domain may be the mechanism underlying HECW2-related disorder.1

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

References

1.PMID 34047014 ↗

ClinVar Variant Classifications

557 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic31

VUS315

Likely Benign137

Benign27

Conflicting19

Pathogenic

Likely Pathogenic

315

VUS

137

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	6	0	0	8
Likely Pathogenic	2	28	1	0	31
VUS	19	283	7	6	315
Likely Benign	0	70	12	55	137
Benign	0	7	8	12	27
Conflicting	—				19
Total	23	394	28	73	537

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

View in ClinVar →

34 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap HECW2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →