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I705 variant in the low density lipoprotein receptor gene has no effect on plasma cholesterol levels
  1. *Centre for Cardiovascular Genetics, The Rayne Institute, University College Hospital Medical School, University College London, 5 University Street, London WC1E 6JJ, UK
  2. †Unit of Clinical Molecular Genetics, Camelia Botnar Laboratories, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK
  3. ‡Medical Research Council Epidemiology and Medical Care Unit, Wolfson Institute of Preventative Medicine, Medical College of St Bartholomew's Hospital, Charterhouse Square, London EC1M 6BQ, UK
  1. Dr Heath, rmhaseh{at}

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Editor—Familial hypercholesterolaemia (FH) is an autosomal dominant inherited lipoprotein disorder characterised by raised plasma low density lipoprotein (LDL) levels, xanthomas, premature coronary heart disease, and a family history of one or more of these. Homozygous FH occurs in one in a million people and they are severely affected, while heterozygotes are moderately affected and occur at a frequency of 1 in 500 in genetically heterogeneous populations. FH is caused by a mutation in the LDL receptor gene (LDLR) and over 700 have been reported1 ( Among these, a missense mutation, T705I in exon 15 (FH Paris-9), was originally reported in a compound heterozygote (“homozygous” FH subject) of French-American origin,2 but has now been observed in several heterozygotes who also carry another mutation in the coding region of the LDL receptor protein.3 4 The presence of the I705 variant has also been reported in two normocholesterolaemic subjects in the heterozygous and homozygous form, which led to the suggestion that the T705I change is a non-FH causing variation.5 The most recent report of this variation was in a Spanish family where the hypercholesterolaemia segregated with the I705 substitution and no other mutation was identified.6Possible explanations for these contradictory findings have been that the exon 15 variant is only pathogenic when another environmental or genetic factor is present, or that in some subjects the I705 variant is in linkage disequilibrium with a second, as yet unidentified causative mutation.

We have set up a clinical genetic diagnostic service for FH7 8 and the I705 variant was identified in a subject with a clinical diagnosis of possible FH who was referred for FH genetic testing (data not shown). To investigate the pathogenicity of the amino acid substitution at codon 705, we have determined the frequency of …

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