rs137852743

Variant names:

• chr2-202467625-T-G
• rs137852743
• NM_001204.7:c.354T>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PS4 PM1_Strong PM5_Supporting PP1 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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 theClinGen Pulmonary Hypertension VCEP: PS3, PS4, PM1_strong, PM2_supporting, PM5_supporting, PP3, PP1 (VCEP specification version v 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA278075/MONDO:0015924/125

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 1.11
• Publications: 27 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 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.
• 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 rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.354T>G	p.Cys118Trp	missense_variant	Exon 3 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.354T>G	p.Cys118Trp	missense_variant	Exon 3 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.354T>G	p.Cys118Trp	missense_variant	Exon 3 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.354T>G	p.Cys118Trp	missense_variant	Exon 3 of 12	2		ENSP00000363702.2
BMPR2	ENST00000479069.1	n.261T>G		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458444 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725766

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108860

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary hypertension, primary, 1 Pathogenic:2

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pulmonary arterial hypertension Pathogenic:1

May 03, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: 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). -

Primary pulmonary hypertension Pathogenic:1

Sep 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 8799). 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%. Experimental studies have shown that this missense change affects BMPR2 function (PMID: 12045205, 25688877). 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	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	2.9	M;M;.
PhyloP100		1.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-11	D;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.96		Loss of disorder (P = 0.0129);Loss of disorder (P = 0.0129);.;
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		1.3
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137852743; hg19: chr2-203332348;