HERC2

Chr 15AR

HECT and RLD domain containing E3 ubiquitin protein ligase 2

Also known as: D15F37S1, MRT38, SHEP1, jdf2, p528

NCBI Gene: 8924 ENSG00000128731 UniProt: O95714 OMIM: 605837

This gene encodes an E3 ubiquitin-protein ligase that regulates DNA damage repair by controlling ubiquitin-dependent retention of repair proteins on damaged chromosomes and modulates iron metabolism and insulin-like growth factor receptor signaling. Biallelic mutations cause autosomal recessive intellectual developmental disorder with onset typically in early childhood. The gene is highly constrained against loss-of-function variants in the general population, indicating that such variants are likely to be pathogenic when present in the homozygous or compound heterozygous state.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene belongs to the HERC gene family that encodes a group of unusually large proteins, which contain multiple structural domains. All members have at least 1 copy of an N-terminal region showing homology to the cell cycle regulator RCC1 and a C-terminal HECT (homologous to E6-AP C terminus) domain found in a number of E3 ubiquitin protein ligases. Genetic variations in this gene are associated with skin/hair/eye pigmentation variability. Multiple pseudogenes of this gene are located on chromosomes 15 and 16. [provided by RefSeq, Mar 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

[Skin/hair/eye pigmentation 1, blond/brown hair]MIM #227220

[Skin/hair/eye pigmentation 1, blue/nonblue eyes]MIM #227220

Intellectual developmental disorder, autosomal recessive 38MIM #615516

Clinical highlights

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.20

LOEUF· LoF intol.

LOF

Mechanism· G2P

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GeneReview available — HERC2