LDLR p.Phe619Ser

The NM_000527.5 (LDLR): c.1856T>C (p.Phe619Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1) PP3 Met: REVEL = 0.832, which is above the threshold for 0.75. PP4 Met: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Moderate Met: Variant meets PM2, and is identified in 6 unrelated index cases who fulfil DLCN criteria for FH from different labs. Two index cases reported from U4M – Lille University &CHRU Lille, University de Lille – CHRU de Lille (SCV000583896.1). Four French index cases reported from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, (SCV000503427.1, PMID20809525). There are two other variants in same codon: LDLR: NM_000527:c.1855T>C (p.Phe619Leu), LDLR: NM_000527:c.1856T>G (p.Phe619Cys), which are classified as Likely Pathogenic by these guidelines. Neither variant is classified as Pathogenic, therefore PM5 is not met.