LDLR p.Arg406Trp

The NM_000527.5(LDLR):c1216C>T (p.Arg406Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS3, PS4, PP1_Strong, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.000097 (0.0097%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.88, which is above the threshold of 0.75. PS3 – Level 1 functional studies: PMID: 2574186; Heterologous cells (CHO), FACS assays - variant results in 60-65% LDLR expression/biosynthesis, LDL binding and LDL internalization compared to wild-type; results meet <70% threshold. PS4 – Variant meets PM2 and is identified in at least 19 unrelated index cases who fulfill clinical criteria for FH (1 case with DLCN criteria from PathWest Laboratory Medicine WA – FH VCEP member lab; 18 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – FH VCEP member lab). PP1_Strong – Variant segregates with phenotype in 31 informative meioses from 15 families in data provided by FH VCEP member labs (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 11 families: 23 affected with the variant and 1 unaffected without the variant; Laboratory of Genetics and Molecular Cardiology – 4 families: 4 affected with the variant and 3 unaffected without the variant). PP4 - Variant meets PM2. Identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) – Likely pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro) – Likely pathogenic by these guidelines. -PM5 not applicable as such variants must be Pathogenic.