ClinVar

Description

The p.I807M variant (also known as c.2421A>G), located in coding exon 14 of the CFTR gene, results from an A to G substitution at nucleotide position 2421. The isoleucine at codon 807 is replaced by methionine, an amino acid with highly similar properties. This variant was found to co-occur with a pathogenic mutation in CFTR and SPINK1 in an individual presenting with chronic pancreatitis (Schneider A et al. Gastroenterology, 2011 Jan;140:162-71). In a cohort of 253 French individuals with idiopathic chronic pancreatitis, two were identified as heterozygous for p.I807M; one was also heterozygous for p.R117H, phase uncertain (Masson E et al. PLoS ONE, 2013 Aug;8:e73522). Another study observed this variant in individuals with pancreatitis and healthy controls at the same frequency (LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376). Functional data demonstrated this variant displayed both maturation of the protein and chloride channel activity similar to that of wild-type protein (Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9; Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077), although bicarbonate permeability and conductance, which are more relevant in the development of pancreatitis, were not assessed. Based on data from gnomAD, the G allele has an overall frequency of approximately 0.07% (148/210958) total alleles studied. The highest observed frequency was 0.52% (77/14800) of South Asian alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.