The variant is an in-frame insertion which consists of a duplication of 18 nucleotides in exon 17, resulting in the in-frame insertion of six amino acids at the end of the transmembrane domain of the receptor protein smaller than whole exon. The variant met PM2 code as absent from controls in Gnomad database

Absent from controls in GnomAD (gnomAD v2.1.1).

variant met PM2 and was found in PMID: 11810272 in one patient with definite FH by SB criteria

variant is located in exon 17

The variant was functionally evaluated in this work (PMID:26220972) by using HepG2 cells transiently transfected with wild-type (WT) or mutant LDLR plasmids. After, the cells were cultured in the presence or absence of the γ-secretase inhibitor (DAPT) in order to study whether the mutations affected γ-secretase cleavage of the transmembrane domain. Western blot analyses of the LDLRs in lysates or in culture media were performed using an antibody against the C-terminal HA tag or an antibody against the ligand-binding domain of the LDLR, This strategy should be able to detect Class 1 (prevent the synthesis of any immunodetectable LDLR) and Class 2 (make the LDLR completely or partially retained in the ER) mutations as well as mutations that affect membrane insertion of the mutant LDLRs. Mutation p.803_808del was found to cause in the lysates a reduced amount of the 120 kDa precursor LDLR form, and an even more reduced amount of the 160 kDa mature LDLR form. This could indicate that this mutant is defective in insertion in the ER membrane and is also rapidly degraded at the cell surface. In addition, the variant appeared to be somewhat defective in γ-secretase cleavage as markedly lower than for the WT-LDLR. In conclusion, as stated by authors, this mutation probably interfere with the normal insertion of the LDLR in the cell membrane. As a consequence, the mutant LDLR may be secreted, may undergo metalloproteinase cleavage leading to ectodomain shedding or may undergo rapid degradation at the cell surface. Whether y-secretase cleavage of the transmembrane domain has any significant biological function is unknown. In addition, although it is unlikely that mutations in the transmembrane domain of the LDLR could affect LDL binding and internalization, authors did not perform any evaluation of these effects. Therefore, BS3 is not Met.