ClinVar

Description

The CFTR c.2856G>C; p.Met952Ile variant (rs151048781) is reported in the literature in multiple individuals with congenital absence of the vas deferens (CBAVD), including in individuals with a second pathogenic CFTR variant (Dayangac 2004, Ratbi 2007, Steiner 2011, Uzun 2005). While this variant has also been reported in several individuals with cystic fibrosis (CF), one individual already carried two other pathogenic variants (Desgeorges 1997, Krenkova 2013). The p.Met952Ile variant is reported in ClinVar (Variation ID: 53580) and is found in the general population with an overall allele frequency of 0.008% (20/251352 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.817). Another variant at this codon (p.Met952Thr) has been reported in individuals with CBAVD and is considered pathogenic (Casals 2000, Gilljam 2004, Wilschanski 2006). Though it is unclear if the p.Met952Ile variant causes classic CF, due to its strong association with CBAVD, this variant is considered to be likely pathogenic. References: Casals T et al. Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum Reprod. 2000; 15(7):1476-83. PMID: 10875853. Dayangac D et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2004 May;19(5):1094-100. PMID: 15070876. Desgeorges M et al. Cystic fibrosis in Lebanon: distribution of CFTR mutations among Arab communities. Hum Genet. 1997 Aug;100(2):279-83. PMID: 9254864. Gilljam M et al. Airway inflammation and infection in congenital bilateral absence of the vas deferens. Am J Respir Crit Care Med. 2004; 169(2):174-9. PMID: 14551163. Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. PMID: 23276700. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007 May;22(5):1285-91. PMID: 17329263. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20. PMID: 21520337. Uzun S et al. Cystic fibrosis transmembrane conductance regulator gene mutations in infertile males with congenital bilateral absence of the vas deferens. Tohoku J Exp Med. 2005 Dec;207(4):279-85. PMID: 16272798. Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006; 174(7):787-94. PMID: 16840743.