Table 3.

Prevalence of Familial Hypercholesterolemia According to Different LDL Cholesterol Thresholds and Mutation Classification Schemes.

LDL Cholesterol Criteria	Mutation Criterion	Prevalence of Familial Hypercholesterolemia
LDL Cholesterol ≥ 190 mg/dl	No mutation required	1,386/20,485 (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	97/20,485 (1 in 211)
LDL Cholesterol ≥ 190 mg/dl	*LDLR loss of function variant; or *Any rare LDLR missense variant	80/20,485 (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	68/20,485 (1 in 301)
No threshold requirement	*LDLR loss of function variant; or *LDLR predicted damaging rare missense variant	60/20,485 (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	24/20,485 (1 in 853)

For each classification scheme, we provide the number who meet the criteria out of a total 20,485 participants (CAD-free controls of the Myocardial Infarction Genetics Consortium combined with CHARGE Consortium participants). Loss of function variants defined as single base changes that introduce a stop codon leading to premature truncation of a protein (nonsense), insertions or deletions (indels) of DNA that scramble the protein translation beyond the variant site (frameshift), or point mutations at sites of pre-mRNA splicing that alter the splicing process (splice-site). Predicted damaging variants refer to those LDLR predicted to be deleterious by each of five 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.