LDLR p.Asp356Val

The variant NM_000527.5(LDLR):c.1067A>T (p.Asp356Val) is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3, PS4_Supporting 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). PP3 - REVEL = 0.903 PS4_Supporting: Variant meets PM2, and is identified in 2 unrelated cases: 1 case with DLCN>6 from PMID: 30745730; 1 case with Simon-Broome criteria of possible FH from Color Health. So, PS4_Supporting is met. 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>C (p.Asp356Ala) (ClinVar ID 251645) - 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.