The single strand conformational polymorphism (SSCP) method was used to screen patients with familial hypercholesterolemia (FH) for mutations in the 3' part of exon 4 of the low density lipoprotein receptor (LDLR) gene. In 311 patients, six previously described mutations were identified in 29 apparently unrelated individuals (9.3%); three of the mutations are null alleles producing no protein, while the other three lead to production of a defective protein. In the patients where no mutation was detected mean total plasma cholesterol levels were 9.4 mmol/l, compared to 11.3 mmol/l in those individuals with a mutation creating a null allele, and 11.2 mmol/l in those with a mutation that resulted in the production of a defective protein (p < 0.001). These data reinforce observations of others that specific mutations in the LDL receptor gene are associated with different effects on plasma lipids, and indicate that the phenotype is influenced by the genotype.