rs876657748

Positions:

• chr2-202520135-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM6 PM2_Supporting PM1 PS3 PS4

This summary comes from the ClinGen Evidence Repository: The c.901T>C variant (NM_001204.7) in BMPR2 is a missense variant predicted to cause substitution of serine by proline at amino acid 301 (p.Ser301Pro). The variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting).The variant has been identified in 5 probands, meeting the PH VCEP threshold for PS4 (>4 pro bands; PMIDs 16429395, 18356561, 25917481, 29743074, and PH VCEP internal lab contributors). The variant has been identified as a de novo occurrence in one individual with pulmonary arterial hypertension and unconfirmed parental relationships (PM6; PMID 29743074). Immunostaining in Hela cells transfected with a FLAG-tagged c.901C>T BMPR2 expression construct demonstrated impaired subcellular trafficking of BMPRII (PMID:25688877) and Western-blot analysis of pulmonary artery smooth muscle cells isolated from a patient with the c.901C>T variant showed no BMP4-induced phosphorylation of Smad1/5/8 (PMID:19324947), indicating an effect on protein function (PS3). This variant resides in a conserved kinase domain (amino acids 203 – 504) but is not defined as a critical residue by the ClinGen PH VCEP (PM1_moderate). In summary, this 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 (specification version 1.0): PS4, PM6, PM2_Supporting, PS3, PM1_moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576586/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 4.54

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 13 ACMG points.

• 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.
• PM6: 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.901T>C	p.Ser301Pro	missense_variant	7/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.901T>C	p.Ser301Pro	missense_variant	7/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.901T>C	p.Ser301Pro	missense_variant	7/13	1	NM_001204.7	ENSP00000363708	P1
BMPR2	ENST00000374574.2	c.901T>C	p.Ser301Pro	missense_variant	7/12	2		ENSP00000363702

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

Pathogenic, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

May 03, 2024

The c.901T>C variant (NM_001204.7) in BMPR2 is a missense variant predicted to cause substitution of serine by proline at amino acid 301 (p.Ser301Pro). The variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). The variant has been identified in 5 probands, meeting the PH VCEP threshold for PS4 (>4 pro bands; PMIDs 16429395, 18356561, 25917481, 29743074, and PH VCEP internal lab contributors). The variant has been identified as a de novo occurrence in one individual with pulmonary arterial hypertension and unconfirmed parental relationships (PM6; PMID 29743074). Immunostaining in Hela cells transfected with a FLAG-tagged c.901C>T BMPR2 expression construct demonstrated impaired subcellular trafficking of BMPRII (PMID: 25688877) and Western-blot analysis of pulmonary artery smooth muscle cells isolated from a patient with the c.901C>T variant showed no BMP4-induced phosphorylation of Smad1/5/8 (PMID: 19324947), indicating an effect on protein function (PS3). This variant resides in a conserved kinase domain (amino acids 203 – 504) but is not defined as a critical residue by the ClinGen PH VCEP (PM1_moderate). In summary, this 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 (specification version 1.0): PS4, PM6, PM2_Supporting, PS3, PM1_moderate). -

Idiopathic and/or familial pulmonary arterial hypertension Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 01, 2020

The p.Ser301Pro variant in BMPR2 has been reported in at least 7 individuals with pulmonary arterial hypertension (PMIDs: 16429395, 19324947, 25917481, 18356561, 29743074, 27816994), and was reported as de novo in one of the individuals (PMID 29743074). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant pulmonary arterial hypertension. ACMG/AMP Criteria applied: PM2, PM6, PS4_Moderate, PP3. -

Pulmonary hypertension, primary, 1 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;.
Eigen	Benign	-0.066
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.92	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.2	N;N;.
REVEL	Uncertain	0.45
Sift	Benign	0.086	T;D;.
Sift4G	Benign	0.080	T;T;.
Polyphen		0.046	B;.;.
Vest4		0.81
MutPred		0.89		Gain of catalytic residue at S301 (P = 0.0047);Gain of catalytic residue at S301 (P = 0.0047);.;
MVP		0.95
MPC		0.48
ClinPred		0.64	D
GERP RS		5.0
Varity_R		0.88
gMVP		0.92

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: rs876657748; hg19: chr2-203384858;