Submissions for variant NM_001204.7(BMPR2):c.354T>G (p.Cys118Trp)

dbSNP: rs137852743

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen	RCV004547471	SCV005043295	pathogenic	Pulmonary arterial hypertension	2024-05-03	reviewed by expert panel	curation	The BMPR2 c.354T>C variant is a missense variant predicted to cause a cysteine to tryptophan substitution at amino acid position 118 (p.Cys118Trp). The variant is absent from gnomAD exomes v.2.1.1 controls and gnomAD genomes v3.0 (PM2_supporting). More than 4 unrelated pulmonary arterial hypertension probands were identified with this variant (PMID: 10973254, PMID: 32255665, PMID: 33007923, and PMID: 31727138) (PS4). In one multigenerational family, the variant segregated with PAH in at least 3 family members (PMID: 10973254) (PP1). BMPR2 p.Cys118Trp is located within the conserved extracellular domain and is a Cys residue critical for protein function (PMID: 9886286, PMID: 12221115, PMID: 12045205, PMID: 16429395) (PM1_strong). Several well-controlled in vitro functional assays provided variant-specific evidence of protein loss of function (PMID: 25688877, PMID: 12221115, and PMID: 32255665) (PS3). In silico prediction (REVEL =0.9279) is consistent with a pathogenic effect for this variant (PP3). Additionally, another variant in the same codon, BMPR2 (NM_001204.7):c.353G>A:(p.Cys118Tyr), was classified as likely pathogenic (PM5_supporting). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PS4, PM1_strong, PM2_supporting, PM5_supporting, PP3, PP1 (VCEP specification version v 1.1, 1/18/2024).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851760	SCV002231540	pathogenic	Primary pulmonary hypertension	2022-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 118 of the BMPR2 protein (p.Cys118Trp). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BMPR2 function (PMID: 12045205, 25688877). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BMPR2 protein function. ClinVar contains an entry for this variant (Variation ID: 8799). This missense change has been observed in individuals with pulmonary hypertension (PMID: 10973254, 31727138). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).
OMIM	RCV000009344	SCV000029562	pathogenic	Pulmonary hypertension, primary, 1	2000-09-01	no assertion criteria provided	literature only
Rare Disease Genomics Group, St George's University of London	RCV000009344	SCV000576046	pathogenic	Pulmonary hypertension, primary, 1		no assertion criteria provided	literature only
Wendy Chung Laboratory, Columbia University Medical Center	RCV001823865	SCV002073581	not provided	Pulmonary arterial hypertension; Idiopathic and/or familial pulmonary arterial hypertension		no assertion provided	literature only