ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000019.9) (NC_000019.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
26482752 This paper is a review. LDLR mutations leading to absent or dysfunctional LDLR at the surface of the hepatocytes result in Familial Hypercholesterolemia (FH), with onset in the 4th decade. Homozygotes have early onset FH.

Haploinsufficiency phenotype comments:

Five different classes of LDLR mutations have been identified, dependent on the effect on the phenotype. Class 1 mutations are null mutations that result in no detectable LDLR protein. In class 2 mutations, the transport of the LDLR from the endoplasmic reticulum to the Golgi apparatus is blocked completely (class 2a) or partially (class 2b). A class 3 mutation leads to expression of a non-functional LDLR. Class 4 mutations result in LDL binding but the LDLR-LDL complexes cannot be internalized, and in class 5 mutations, recycling of the LDLR is not efficient and therefore do not reach the cell surface (PMID: 26482752). LDLR is subject to Alu-mediated partial gene duplications. Multiple (~66) gross insertions and duplications (some publications: PMID: 22698793 (ex. 2-15), PMID: 23669246 (ex. 2-8), PMID: 20145306 (ex. 3-12), PMID: 11313767 (ex. 8-10), PMID: 23415438 (ex. 7-12), and PMID: 25461735 (prom.-ex. 6). These mutations lead to dysfunction of the LDLR protein.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

There are no reports of disease associated complete LDLR gene duplications.