ClinVar

Description

The p.C82F variant (also known as c.245G>T), located in coding exon 3 of the BMPR1A gene, results from a G to T substitution at nucleotide position 245. The cysteine at codon 82 is replaced by phenylalanine, an amino acid with highly dissimilar properties. An alteration, p.C82Y, in the same codon has been reported in a patient who met clinical criteria for juvenile polyposis syndrome and functional studies in a human kidney cell line demonstrated the variant protein had reduced bone morphogenetic protein signaling and deficient subcellular localization when compared to wild type (Howe JR et al. J. Surg. Res., 2013 Oct;184:739-45; Calva-Cerqueira D et al. Clin. Genet., 2009 Jan;75:79-85). Based on internal structural analysis, this alteration is predicted to be structurally destabilizing due to the loss of a cysteine-cysteine bridge (Keller S et al. Nat. Struct. Mol. Biol., 2004 May;11:481-8). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 85000 alleles tested) in our clinical cohort. 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 the majority of available evidence to date, this variant is likely to be pathogenic.