ClinVar Miner

Submissions for variant NM_001204.7(BMPR2):c.1487G>A (p.Cys496Tyr) (rs1085307362)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508026 SCV000602647 likely pathogenic none provided 2019-12-24 criteria provided, single submitter clinical testing The BMPR2 c.1487G>A; p.Cys496Tyr variant (rs1085307362) is reported in the literature in an individual with a personal and family history of pulmonary arterial hypertension (PAH) (Machado 2006). Functional data indicate that this variant, like other cysteine substitution variants in the kinase domain of BMPR2, results in a disruption of trafficking to the plasma membrane, with the majority of protein localized to the endoplasmic reticulum (John 2015). The p.Cys496Tyr variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 496 is highly conserved, it occurs in the functionally important kinase domain of BMPR2, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another amino acid substitution at this codon (p.Cys496Arg) has been reported in individuals with PAH (Machado 2015, Yang 2018). Based on available information, the p.Cys496Tyr variant is considered to be likely pathogenic. References: John et al. Defective cellular trafficking of the bone morphogenetic protein receptor type II by mutations underlying familial pulmonary arterial hypertension. Gene. 2015; 561(1): 148-156. Machado et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006; 27(2): 121-132. Machado et al. Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Hum Mutat. 2015; 36(12): 1113-1127. Yang H et al. Genetic analyses in a cohort of 191 pulmonary arterial hypertension patients. Respir Res. 2018 May 9;19(1):87.
Medical & Molecular Genetics Group,University of Lincoln RCV000488722 SCV000576254 pathogenic Primary pulmonary hypertension 1 no assertion criteria provided literature only

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