ClinVar

In 2 presumably unrelated families with mild cystic fibrosis (CF; 219700), Dean et al. (1990) found a 482G-A transition in exon 4 of the CFTR gene, resulting in an arg117-to-his (R117H) substitution.

Gervais et al. (1993) reported that the R117H mutation was present in 4 of 23 patients with congenital absence of the vas deferens (CBAVD; 277180). Three patients had compound heterozygosity for R117H and delF508 (602421.0001), whereas a fourth was a compound heterozygote for R117H and 2322delG. None of the 23 patients had pulmonary evidence of cystic fibrosis. Five patients without the delF508 mutation had unilateral renal agenesis in addition to absence of the vas deferens; these patients may represent a different distinct subset. Bienvenu et al. (1993) described for the first time homozygosity for the R117H mutation in a 30-year-old French male with sterility owing to congenital bilateral absence of the vas deferens. The subject had no respiratory or pancreatic involvement and had a normal sweat electrolyte value. His parents were not consanguineous, and there were no other cases of CBAVD or CF in the family.

Kiesewetter et al. (1993) presented evidence that the chromosome background of the R117H mutation has a profound effect on the phenotype produced. Three length variants of CFTR have been observed with varying degrees of exon 9 splicing depending on variation in the length of the polypyrimidine tract in the splice acceptor site in intron 8 (Chu et al., 1991, 1993). Varied lengths of a thymidine (T)-tract (5, 7, or 9Ts) were noted in front of the splice acceptor site of intron 8. The 5T variant is present in 5% of the CFTR alleles among Caucasian populations producing almost exclusively (95%) exon 9-minus RNA. The effect of this T-tract polymorphism in CFTR gene expression was also documented by its relationship with the R117H mutation: R117H (5T) is found in typical CF patients with pancreatic sufficiency; R117H (7T) is associated with CBAVD. The R117H mutation has been reported in CF patients, males with congenital bilateral absence of the vas deferens, and in an asymptomatic woman. Furthermore, population screening discovered a 19-fold higher than expected number of carriers of this CF mutation. The situation was compared to that in Gaucher disease in which the severity of neuronopathic disease associated with a missense mutation appears to be altered by additional missense mutations in the same allele (Latham et al., 1990).

White et al. (2001) reported a healthy 29-year-old female who was found to be an R117H/delF508 heterozygote. The patient had atopic asthma and infertility, but normal height and weight and no pulmonary symptoms of CF. Analysis of the polythymidine tract showed that the R117H mutation was in cis with a 7T tract and the delta-F508 mutation in cis with a 9T tract. The authors concluded that poly-T studies are important in any patient found to have the R117H mutation, and recommended caution in the genetic counseling of such families.

Thauvin-Robinet et al. (2009) reported the results of a national collaborative study in France to establish the overall phenotype associated with R117H and to evaluate the disease penetrance of the R117H+F508del genotype. In 184 R117H+F508del individuals of the French population, including 72 newborns, the disease phenotype was predominantly mild; 1 child had classic cystic fibrosis, and 3 adults had severe pulmonary symptoms. In 5,245 healthy adults with no family history of CF, the allelic prevalence of F508del was 1.06%, R117H;T7 0.27%, and R117H;T5 less than 0.01%. The theoretical number of R117H;T7+F508del individuals in the French populations was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classic CF for R117H;T7+F508del was estimated at 0.03% and that of severe CF in adulthood at 0.06%. Thauvin-Robinet et al. (2009) suggested that R117H should be withdrawn from CF mutation panels used for screening programs.