ClinVar

Description

The BMPR1A p.Thr78Ile variant was identified in 3 of 378 proband chromosomes (frequency: 0.008) from individuals or families with juvenile polyposis (Howe 2004, Calva-Cerqueira 2009, Huang 2010). The variant was also identified in dbSNP (ID: rs1064793490) as "With uncertain significance allele", in ClinVar (classified as uncertain significance by GeneDx) and in the LOVD 3.0 database (6x effect unknown). It was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). A case report identified the mutation in an individual with juvenile polyposis and predicted the substitution of the amino acid threonine to isoleucine at codon 233 would result in the loss of BMP-mediated intracellular signaling (Kurland 2007). Data from an in vitro model demonstrated that the total level of BMPR1A protein by ELISA was comparable between the wild-type and the missense construct, although the missense construct had reduced bone morphogenetic protein (BMP) pathway signaling activity and demonstrated near-complete intracellular localization compared to the predominant membrane localization of the wild-type (Howe 2013). The p.Thr78 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Thr78Ile variant occurs in the first base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.