ClinVar Genomic variation as it relates to human health

The p.R119C variant (also known as c.355C>T), located in coding exon 4 of the BMPR1A gene, results from a C to T substitution at nucleotide position 355. The arginine at codon 119 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with BMPR1A-related disease (Aretz S et al. J Med Genet, 2007 Nov;44:702-9; Zhao ZY et al. Gastroenterol Rep (Oxf), 2023 Jan;11:goac082; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17873119, 10881198, 22799562, 23433720, 33032550, 28152038)

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17873119, 36632626, 37354305].

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 119 of the BMPR1A protein (p.Arg119Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with juvenile polyposis syndrome (PMID: 17873119; Invitae). ClinVar contains an entry for this variant (Variation ID: 142484). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BMPR1A function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

This missense variant replaces arginine with cysteine at codon 119 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with juvenile polyposis syndrome and BMPR1A-related disease (PMID: 17873119, 36632626; ClinVar SCV000945914.5, SCV000186643.9). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The BMPR1A c.355C>T; p.Arg119Cys variant (rs587782494) is reported in the literature in individuals affected with juvenile polyposis syndrome (JPS), attenuated familial adenomatous polyposis, and early onset colorectal cancer (Aretz 2007, Jelsig 2023, Yildiz 2023, Zhao 2023), and was apparently de novo variant in one individual (Zhao 2023). The variant also segregated in a family member who presented with JPS (Zhao 2023). This variant is also reported in ClinVar (Variation ID: 142484). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.825). Based on available information, this variant is considered to be likely pathogenic. References: Aretz S et al. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. 2007 Nov;44(11):702-9. PMID: 17873119. Jelsig AM et al. Whole genome sequencing and disease pattern in patients with juvenile polyposis syndrome: a nationwide study. Fam Cancer. 2023 Oct;22(4):429-436. PMID: 37354305. Yildiz S et al. Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer. Front Oncol. 2023 Oct 27;13:1253867. PMID: 37965459. Zhao ZY et al. Re-recognition of BMPR1A-related polyposis: beyond juvenile polyposis and hereditary mixed polyposis syndrome. Gastroenterol Rep (Oxf). 2023 Jan 5;11:goac082. PMID: 36632626.