rs1085307324

Variant names:

• chr2-202532714-T-C
• rs1085307324
• NM_001204.7:c.1258T>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1_Supporting PS4 PS3 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: BMPR2 c.1258T>C is a missense variant predicted to cause substitution of cysteine to arginine at amino acid position 420 (p.Cys420Arg). This variant resides within the catalytic kinase domain but is not a known critical residue (PM1_moderate met). The variant is absent in gnomAD databases, meeting PM2_supporting criterion (BA1 and BS1 not met). The REVEL score of 0.934 meets PP3_suporting criteria (>=0.75) (BP4 not met). Functional studies indicated subcellular mislocalization of the mutant protein (PMID:25688877) and decreased receptor-mediated signaling (PMID:12045205) (PS3 met). At least five unrelated probands have been reported in the literature (PMID:11115378, 21801371, 27587546, 32634488, 32966279), meeting the PS4 threshold of >4 probands. Alternative missense variants have been reported in the same location but these variants are pending expert panel curation and PM5 is not scored at this time. 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: PS4_strong, PS3_strong, PM1_ moderate, PM2_supporting, PP3 (VCEP specification version 1.1.0, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350341977/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 31)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.73

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 11 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.
• 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.1258T>C	p.Cys420Arg	missense_variant	Exon 9 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1258T>C	p.Cys420Arg	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.1258T>C	p.Cys420Arg	missense_variant	Exon 9 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1258T>C	p.Cys420Arg	missense_variant	Exon 9 of 12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

Jan 22, 2025

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

BMPR2 c.1258T>C is a missense variant predicted to cause substitution of cysteine to arginine at amino acid position 420 (p.Cys420Arg). This variant resides within the catalytic kinase domain but is not a known critical residue (PM1_moderate met). The variant is absent in gnomAD databases, meeting PM2_supporting criterion (BA1 and BS1 not met). The REVEL score of 0.934 meets PP3_suporting criteria (>=0.75) (BP4 not met). Functional studies indicated subcellular mislocalization of the mutant protein (PMID: 25688877) and decreased receptor-mediated signaling (PMID: 12045205) (PS3 met). At least five unrelated probands have been reported in the literature (PMID: 11115378, 21801371, 27587546, 32634488, 32966279), meeting the PS4 threshold of >4 probands. Alternative missense variants have been reported in the same location but these variants are pending expert panel curation and PM5 is not scored at this time. 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: PS4_strong, PS3_strong, PM1_ moderate, PM2_supporting, PP3 (VCEP specification version 1.1.0, 1/18/2024). -

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	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-11	D;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0090	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.91
MutPred		0.87		Loss of catalytic residue at M418 (P = 3e-04);Loss of catalytic residue at M418 (P = 3e-04);.;
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
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: rs1085307324; hg19: chr2-203397437; COSMIC: COSV101001478;