rs1085307325

Variant names:

• chr2-202532715-G-A
• rs1085307325
• NM_001204.7:c.1259G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS4_Moderate PM1 PM5 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: BMPR2 c.1259G>A is a missense variant predicted to cause substitution of cysteine to tyrosine at amino acid position 420 (p.Cys420Tyr). The variant is absent from gnomAD v2.1.1 and v4.1 (PM2_supporting). A REVEL score of 0.924 meets PP3_supporting (>0.75). This variant resides within the conserved catalytic kinase domain but does not affect a known critical residue (PM1_moderate). The variant has been reported in four unrelated PAH probands (PMID:15146475, 16429395, 21737554) with additional citations referring back to the same individuals (PMID:21801371, 32634488, 30578397) (PS4_moderate). A different missense variant at the same amino acid residue, p.Cys420Arg (PMID:11115378, 21801371) was previously classified by the PH VCEP as pathogenic (PM5_moderate). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS4_moderate, PM1_moderate, PM5_moderate, PM2_supporting, PP3_supporting (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350341979/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 31)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.64
• Publications: 5 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: Likely_pathogenic. The variant received 8 ACMG points.

• 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.
• 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.1259G>A	p.Cys420Tyr	missense_variant	Exon 9 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1259G>A	p.Cys420Tyr	missense_variant	Exon 9 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1259G>A	p.Cys420Tyr	missense_variant	Exon 9 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1259G>A	p.Cys420Tyr	missense_variant	Exon 9 of 12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

Apr 29, 2025

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

BMPR2 c.1259G>A is a missense variant predicted to cause substitution of cysteine to tyrosine at amino acid position 420 (p.Cys420Tyr). The variant is absent from gnomAD v2.1.1 and v4.1 (PM2_supporting). A REVEL score of 0.924 meets PP3_supporting (>0.75). This variant resides within the conserved catalytic kinase domain but does not affect a known critical residue (PM1_moderate). The variant has been reported in four unrelated PAH probands (PMID: 15146475, 16429395, 21737554) with additional citations referring back to the same individuals (PMID: 21801371, 32634488, 30578397) (PS4_moderate). A different missense variant at the same amino acid residue, p.Cys420Arg (PMID: 11115378, 21801371) was previously classified by the PH VCEP as pathogenic (PM5_moderate). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS4_moderate, PM1_moderate, PM5_moderate, PM2_supporting, PP3_supporting (VCEP specification version 1.1, 1/18/2024). -

Primary pulmonary hypertension Pathogenic:1

Feb 28, 2022

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 tyrosine, which is neutral and polar, at codon 420 of the BMPR2 protein (p.Cys420Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pulmonary arterial hypertension (PMID: 15146475, 21737554, 21801371; Invitae). ClinVar contains an entry for this variant (Variation ID: 425907). 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. This variant disrupts the p.Cys420 amino acid residue in BMPR2. Other variant(s) that disrupt this residue have been observed in individuals with BMPR2-related conditions (PMID: 21801371, 27453251), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Pulmonary hypertension, primary, 1 Pathogenic:1

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.1	M;M;.
PhyloP100		9.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-11	D;D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.013	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.93
MutPred		0.87		Loss of catalytic residue at M418 (P = 1e-04);Loss of catalytic residue at M418 (P = 1e-04);.;
MVP		0.99
MPC		1.4
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.95
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1085307325; hg19: chr2-203397438; COSMIC: COSV101001450;