Table 3

Prevalence of FH According to Different LDL Cholesterol Thresholds and Mutation Classification Schemes

LDL Cholesterol CriteriaMutation CriterionPrevalence of FH
LDL cholesterol ≥190 mg/dlNo mutation required1,386 of 20,485 (1 in 14)
No threshold requirement•LDLR loss-of-function variant; or
LDLR predicted damaging rare missense variant; or
LDLR, APOB, PCSK9 variant pathogenic in ClinVar
97 of 20,485 (1 in 211)
LDL cholesterol ≥190 mg/dl•LDLR loss-of-function variant; or
•any rare LDLR missense variant
80 of 20,485 (1 in 256)
LDL cholesterol ≥130 mg/dl•LDLR loss-of-function variant: or
LDLR predicted damaging rare, missense variant; or
LDLR, APOB, PCSK9 variant pathogenic in ClinVar
68 of 20,485 (1 in 301)
No threshold requirement•LDLR loss-of-function variant; or
LDLR predicted damaging rare missense variant
60 of 20,485 (1 in 341)
LDL cholesterol ≥190 mg/dl•LDLR loss-of-function variant; or
LDLR predicted damaging rare missense variant; or
LDLR, APOB, PCSK9 variant pathogenic in ClinVar
24 of 20,485 (1 in 853)

For each classification scheme, the number of participants who met the criteria among a total of 20,485 participants (CAD-free control subjects of the Myocardial Infarction Genetics Consortium combined with CHARGE Consortium participants) is provided. Loss-of-function variants were defined as single-base changes that introduce a stop codon that leads to premature truncation of a protein (nonsense), insertions or deletions (indels) of DNA that scramble protein translation beyond the variant site (frameshift), or point mutations at sites of pre-messenger ribonucleic acid splicing that alter the splicing process (splice site). Predicted damaging variants refer to those LDLR predicted to be deleterious by each of 5 in silico prediction algorithms (LRT score, MutationTaster, PolyPhen-2 HumDiv, PolyPhen-2 HumVar, and Sorting Intolerant From Tolerant [SIFT]). Rare variants refers to those with minor allele frequency <1% in the sequenced population.

APOB = apolipoprotein B; LDLR = low-density lipoprotein receptor; PCSK9 = proprotein convertase subtilisin/kexin type 9; other abbreviations as in Tables 1 and 2.