rs137852749

Positions:

• chr2-202552774-G-A
• chr2-202552774-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS3_Supporting PP1 PP3 PM5 PM2_Supporting PS4 PS2 PM1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_001204.7(BMPR2):c.1472G>A (p.Arg491Gln) variant is a missense variant predicted to cause an arginine to glutamine substitution at amino acid position 491. The variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). The variant co-segregated with PAH in a large Iberian family with at least four confirmed meioses (PP1; PMID:30894412), is recurrent in more than four unrelated PAH patients (PS4; PMID:20534176 and PMID:29023671) and confirmed de novo in at least two probands with unaffected parents (PS2; PMID:10903931 and PMID:23298310). c.1472G>A resides in the conserved kinase domain of BMPR-II and changes an invariant and critical arginine residue at position 491 (PM1_Strong; PMID:7768349, PMID:34400635), likely impairing interaction with other BMP receptors. The functional assay evidence for a role in BMP receptor interactions was based on a PH VCEP approved luciferase activity assay but lacked known pathogenic and benign variant controls, so PS3 was scored at the supporting level (PS3_supporting; PMID:18321866). A different amino acid change at the same position (p.Arg491Trp) was classified as pathogenic (PM5). PP3 was met based on a REVEL score of 0.962. In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS2, PS3_supporting, PS4, PM1_strong, PM2_supporting, PM5, PP1, PP3 (VCEP specification version v 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA278089/MONDO:0015924/125

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BMPR2 ENST00000374580.10 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 O:1
• Conservation: PhyloP100: 10.0

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 18 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.1472G>A	p.Arg491Gln	missense_variant	11/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1472G>A	p.Arg491Gln	missense_variant	11/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1472G>A	p.Arg491Gln	missense_variant	11/13	1	NM_001204.7	ENSP00000363708	P1
BMPR2	ENST00000374574.2	c.1472G>A	p.Arg491Gln	missense_variant	11/12	2		ENSP00000363702

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary hypertension, primary, 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Hannover Medical School	Jun 11, 2024	- -
Pathogenic, no assertion criteria provided	literature only	Rare Disease Genomics Group, St George's University of London	-	- -

Pulmonary arterial hypertension Pathogenic:2

Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	-	- -
Pathogenic, reviewed by expert panel	curation	Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen	May 03, 2024	The NM_001204.7(BMPR2):c.1472G>A (p.Arg491Gln) variant is a missense variant predicted to cause an arginine to glutamine substitution at amino acid position 491. The variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). The variant co-segregated with PAH in a large Iberian family with at least four confirmed meioses (PP1; PMID: 30894412), is recurrent in more than four unrelated PAH patients (PS4; PMID: 20534176 and PMID: 29023671) and confirmed de novo in at least two probands with unaffected parents (PS2; PMID: 10903931 and PMID: 23298310). c.1472G>A resides in the conserved kinase domain of BMPR-II and changes an invariant and critical arginine residue at position 491 (PM1_Strong; PMID: 7768349, PMID: 34400635), likely impairing interaction with other BMP receptors. The functional assay evidence for a role in BMP receptor interactions was based on a PH VCEP approved luciferase activity assay but lacked known pathogenic and benign variant controls, so PS3 was scored at the supporting level (PS3_supporting; PMID: 18321866). A different amino acid change at the same position (p.Arg491Trp) was classified as pathogenic (PM5). PP3 was met based on a REVEL score of 0.962. In summary, this variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS2, PS3_supporting, PS4, PM1_strong, PM2_supporting, PM5, PP1, PP3 (VCEP specification version v 1.1, 1/18/2024). -

Pulmonary venoocclusive disease 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

-

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.55). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008806 / PMID: 10903931). Different missense changes at the same codon (p.Arg491Leu, p.Arg491Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008802, VCV001067745 / PMID: 10903931). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 28, 2019

The BMPR2 c.1472G>A; p.Arg491Gln variant (rs137852749) is reported in the literature in multiple individuals affected with familial and sporadic forms of pulmonary arterial hypertension (PAH) (Deng 2000, Liu 2012, Machado 2006, Pfarr 2011, Rosenzweig 2008, Sztrymf 2008). This variant is reported as pathogenic in ClinVar (Variation ID: 8806), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 491 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional assays show that while the variant protein is trafficked appropriately to the plasma membrane, there is a decrease in ligand-dependent activation of a downstream SMAD reporter (Rudarakanchana 2002). Additionally, another variant at this codon (c.1471C>T, p.Arg491Trp) has been reported in individuals with PAH (Deng 2000, Liu 2012, Machado 2006, Pfarr 2011, Rosenzweig 2008, Sztrymf 2008), and codon 491 is considered a mutational hotspot (Wong 2006). Based on available information, this variant is considered to be pathogenic. References: Deng et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000; 67(3): 737-744. Liu D et al. Molecular genetics and clinical features of Chinese idiopathic and heritable pulmonary arterial hypertension patients. Eur Respir J. 2012 Mar;39(3):597-603. Machado et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006; 27(2): 121-132. Pfarr N et al. Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations. Respir Res. 2011 Jul 29;12:99. Rosenzweig et al. Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. J Heart Lung Transplant. 2008; 27(6): 668-674. Rudarakanchana et al. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet. 2002; 11(13): 1517-1525. Sztrymf et al. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med. 2008; 177(12): 1377-1383. Wong et al. Evolutionary conservation and mutational spectrum of BMPR2 gene. Gene. 2006; 368: 84-93. -

Primary pulmonary hypertension Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 07, 2023

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: 8806). This missense change has been observed in individual(s) with primary pulmonary hypertension (PMID: 10903931, 32581362). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 491 of the BMPR2 protein (p.Arg491Gln). This variant disrupts the p.Arg491 amino acid residue in BMPR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10903931, 12045205, 28388887, 31727138; 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

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	H;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	D;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.95		Loss of phosphorylation at T493 (P = 0.0818);Loss of phosphorylation at T493 (P = 0.0818);.;
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.97

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: rs137852749; hg19: chr2-203417497; COSMIC: COSV65808679;