Submissions for variant NM_001204.7(BMPR2):c.908G>A (p.Arg303His)

gnomAD frequency: 0.00004  dbSNP: rs200948870

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
AiLife Diagnostics, AiLife Diagnostics	RCV002223216	SCV002501148	uncertain significance	not provided	2022-01-21	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000488504	SCV002768180	uncertain significance	Pulmonary hypertension, primary, 1	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial primary pulmonary hypertension 1, with or without HHT (MIM#178600), primary fenfluramine or dexfenfluramine-associated pulmonary hypertension (MIM#178600) and pulmonary venoocclusive disease 1 (MIM#265450). However, gain of function has been noted in relation to upregulation of p38 MAPK-dependent pro-proliferative pathways and dominant negative has also been suggested as a mechanism in relation to SMAD signalling (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been reported for pulmonary arterial hypertension (PMID: 33380512). (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Arg303Cys): 2 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated protein kinase domain (UniProt). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg303Cys) variant has been reported in one individual with congenital heart disease and pulmonary arterial hypertension (PMID: 27002414). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported in one individual with pulmonary arterial hypertension (PMID: 16429395). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs carrying the p.(Arg303His) variant were retained in the endoplasmic reticulum compared to WT constructs that were localised to the plasma membrane. Additionally, mutant protein also demonstrated incomplete post-translational modification compared to WT protein (PMID: 25688877). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002481548	SCV002786209	uncertain significance	Pulmonary hypertension, primary, 1; Pulmonary venoocclusive disease 1	2021-10-19	criteria provided, single submitter	clinical testing
Rare Disease Genomics Group, St George's University of London	RCV000488504	SCV000576129	pathogenic	Pulmonary hypertension, primary, 1		no assertion criteria provided	literature only