LDLR p.Asp356Ala

The variant NM_000527.5(LDLR):c.1067A>C (p.Asp356Ala) is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP1, PP3, and PP4 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 - This variant is absent from gnomAD (gnomAD v2.1.1). PP1 - variant segregates with FH phenotype in 2 informative meiosis in 1 family from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obeste et des Dyslipidemies (APHP Sorbonne Univeristie Hopitalde la Pitie-Salpetriere): 2 affected family members have the variant. PP3 - REVEL=0.947 PP4 - Variant meets PM2 and is identified in at least 1 index case meeting clinical diagnostic criteria for FH, after alternative causes of high cholesterol were excluded. PM5: 4 other missense variants in the same codon: 1) NM_000527.5(LDLR):c.1066G>T (p.Asp356Tyr) (ClinVar ID 226345) - Pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1066G>C (p.Asp356His) (ClinVar ID 251644) - Likely Pathogenic by these guidelines. 3) NM_000527.5(LDLR):c.1066G>A (p.Asp356Asn) (ClinVar ID 251643) - Unknown Significance by these guidelines. 4) NM_000527.5(LDLR):c.1067A>T (p.Asp356Val) (ClinVar ID 440623) - Likely Pathogenic by these guidelines. There is 1 variant (p.Asp356Tyr) in the same codon classified as Pathogenic by these guidelines. So PM5 is met.