rs137852746

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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. 13/22 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 2.52

Publications

25 publications found

Variant links:

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]

BMPR2 Gene-Disease associations (from GenCC):

pulmonary arterial hypertension
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
pulmonary hypertension, primary, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
heritable pulmonary arterial hypertension
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

BMPR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 VariationId is 8806.Status of the report is reviewed_by_expert_panel, 3 stars.

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 VariationId is 8802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7 link	c.1471C>T	p.Arg491Trp	missense_variant	Exon 11 of 13	ENST00000374580.10	NP_001195.2	Q13873-1
BMPR2	XM_011511687.2 link	c.1471C>T	p.Arg491Trp	missense_variant	Exon 11 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10 link	c.1471C>T	p.Arg491Trp	missense_variant	Exon 11 of 13	1	NM_001204.7	ENSP00000363708.4		Q13873-1
BMPR2	ENST00000374574.2 link	c.1471C>T	p.Arg491Trp	missense_variant	Exon 11 of 12	2		ENSP00000363702.2		Q13873-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pulmonary hypertension, primary, 1

Pathogenic:3

Jul 11, 2016

Center for Genomic Medicine, Kyoto University Graduate School of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Rare Disease Genomics Group, St George's University of London

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Pulmonary arterial hypertension

Pathogenic:2

Sep 26, 2022

John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

BMPR2-related disorder

Pathogenic:1

Mar 21, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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, 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. -

Pulmonary venoocclusive disease 1;C4552070:Pulmonary hypertension, primary, 1

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PP3+PM5+PS4+PM1_Strong -

not provided

Pathogenic:1

Apr 11, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this BMPR2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 19,619 individuals referred to our laboratory for BMPR2 testing. ClinVar contains an entry for this variant (Variation ID: 8802). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt BMPR2 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 (internal data). 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

Wendy Chung Laboratory, Boston Children's Hospital

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

D;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.4

H;H;.

PhyloP100

2.5

PrimateAI

Pathogenic

0.92

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

GERP RS

4.6

Varity_R

0.97

gMVP

0.98

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over