Goodeve (2010) noted that mutations in the VWF gene, which were sometimes numbered from the transcription start site of the mature protein, are now 'numbered from the first A of the ATG initiator methionine codon (A = +1) at the start of every protein (Met = +1), with cDNA rather than genomic DNA being commonly used as a reference sequence.' Thus, the mutation originally designated ARG91GLN is now designated ARG854GLN (R854Q).
In a patient with the Normandy type of von Willebrand disease (VWD2N; see 613554), Gaucher et al. (1991) demonstrated compound heterozygosity for the arg53-to-trp mutation (193400.0012) and another C-to-T transition that resulted in a substitution of glutamine for arginine-91. The patient's parents were related as second cousins.
Hilbert et al. (2004) reported 2 unrelated French patients with type 2N VWD who were compound heterozygous for R854Q and another pathogenic mutation (Y795C, 613160.0031 and C804F, 613160.0032, respectively).
Peerlinck et al. (1992) identified a heterozygous A-to-G transition in exon 20 of the VWF gene, resulting in an arg854-to-gln (R854Q) substitution, in a 23-year-old woman with a lifelong history of bleeding and low VWF levels, consistent with von Willebrand disease type 1 (193400). Laboratory studies showed disproportionately low factor VIII (F8; 300841) and decreased binding capacity of VWF for F8. The R854Q substitution occurred in the putative factor VIII-binding domain. All VWF multimers were normal. Neither parent was clinically affected, but laboratory studies showed that the father had partially increased bleeding time and partially decreased VWF antigen. Restriction enzyme analysis indicated that the unaffected mother was also heterozygous for the R854Q mutation, and that the patient had inherited a hypomorphic 'silent' VWF allele from her father. Peerlinck et al. (1992) noted that the inheritance pattern in this family was difficult to determine, but concluded that the presence of the 'silent' allele allowed the clinical expression of the mutated second allele, resulting in a recessive phenotype in the proband. Peerlinck et al. (1992) commented that although the phenotype was similar to that of the 'Normandy' type 2N variant (see 613554), the patient also had quantitatively low VWF and was thus classified as having VWD type 1.
