rs137852746

chr2-202552773-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001204.7(BMPR2):c.1471C>T(p.Arg491Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R491Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 2.52

Genes affected

BMPR2 (HGNC:1078): (bone morphogenetic protein receptor type 2) This gene encodes a member of the bone morphogenetic protein (BMP) receptor family of transmembrane serine/threonine kinases. The ligands of this receptor are members of the TGF-beta superfamily. BMPs are involved in endochondral bone formation and embryogenesis. These proteins transduce their signals through the formation of heteromeric complexes of two different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Mutations in this gene have been associated with primary pulmonary hypertension, both familial and fenfluramine-associated, and with pulmonary venoocclusive disease. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001204.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-202552774-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8806.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, BMPR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 2-202552773-C-T is Pathogenic according to our data. Variant chr2-202552773-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-202552773-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR2	NM_001204.7	c.1471C>T	p.Arg491Trp	missense_variant	11/13	ENST00000374580.10
BMPR2	XM_011511687.2	c.1471C>T	p.Arg491Trp	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10	c.1471C>T	p.Arg491Trp	missense_variant	11/13	1	NM_001204.7	P1
BMPR2	ENST00000374574.2	c.1471C>T	p.Arg491Trp	missense_variant	11/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pulmonary hypertension, primary, 1 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -
Pathogenic, no assertion criteria provided	literature only	Rare Disease Genomics Group, St George's University of London	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Center for Genomic Medicine, Kyoto University Graduate School of Medicine	Jul 11, 2016	- -

Pulmonary arterial hypertension Pathogenic:2

Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine	Sep 26, 2022	- -

BMPR2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2023

The BMPR2 c.1471C>T variant is predicted to result in the amino acid substitution p.Arg491Trp. This variant has been reported in patients with pulmonary arterial hypertension (PAH) (e.g., Liu et al. 2011. PubMed ID: 21737554; Ghigna et al. 2016. PubMed ID: 27811071; Yang et al. 2018. PubMed ID: 29743074; Wang et al. 2019. PubMed ID: 30578397, see Supplementary Dataset 1). An alternate substitution of the same amino acid (p.Arg491Gln) has also been reported in PAH patients (Liu et al. 2011. PubMed ID: 21737554). The p.Arg491 amino acid is located in the BMPR2 kinase domain, and alterations of this amino acid have been reported to disrupt downstream signaling (Rudarakanchana et al. 2002. PubMed ID: 12045205; Dewachter et al. 2009. PubMed ID: 19324947). This variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Several outside laboratories have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/8802/). This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant inhibits Smad pathway activation and leads to disruption of other downstream signalling pathways (Rudarakanchana et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27587546, 21737554, 32634488, 35346192, 32581362, 19324947, 25688877, 27811071, 29843651, 28388887, 29743074, 30578397, 26387786, 14985116, 20002458, 15591269, 16429395, 11502704, 12045205, 20534176, 18356561, 15059534, 16002577, 10903931, 18503968, 31727138, 32966279, 33066286, 21801371) -

Primary pulmonary hypertension Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 491 of the BMPR2 protein (p.Arg491Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pulmonary hypertension (PMID: 10903931, 28388887). ClinVar contains an entry for this variant (Variation ID: 8802). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg491 amino acid residue in BMPR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Pulmonary arterial hypertension;C5679820:Idiopathic and/or familial pulmonary arterial hypertension Other:1

not provided, no classification provided

literature only

Wendy Chung Laboratory, Columbia University Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.4	H;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.6	D;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.93		Gain of catalytic residue at R491 (P = 0.0011);Gain of catalytic residue at R491 (P = 0.0011);.;
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137852746; hg19: chr2-203417496; COSMIC: COSV65808187;