rs1085308077

Variant names:

• chr2-202532612-G-C
• rs1085307306
• NM_001204.7:c.1156G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-202532612-G-C
• chr2-202532612-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1_Strong PM5_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.1156G>C variant is a missense variant predicted to cause a glutamic acid to glutamine substitution at amino acid position 386. The variant is absent from the gnomAD v2.1.1 control and v4.1.0 populations (PM2_supporting). Only one patient with the variant has been reported (PMID:26387786), and therefore, PS4 is not met. Glu386Gln is located in the catalytic kinase domain and is known to be an indispensable residue (PM1_strong). Other likely pathogenic missense variants causing a different amino acid change at the same residue have been reported, including Glu386Lys, Glu386Ala, Glu386Val, and Glu386Gly (PM5_supporting). Computational evidence for pathogenicity included a REVEL score of 0.961, which meets the threshold of >0.75 defined by the ClinGen Pulmonary Hypertension VCEP, and AlphaMissense 0.9837 (PP3 met but not BP4). Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation evidence. Similarly, functional data is unavailable for this variant, so BS3 and PS3 were not evaluated. In summary, this variant meets the criteria to be classified as likely pathogenic (LP) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_strong, PM2_supporting, PM5_supporting, and PP3 (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350341737/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

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 Likely_pathogenic. Variant got 7 ACMG points.

• 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.1156G>C	p.Glu386Gln	missense_variant	Exon 9 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1156G>C	p.Glu386Gln	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.1156G>C	p.Glu386Gln	missense_variant	Exon 9 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1156G>C	p.Glu386Gln	missense_variant	Exon 9 of 12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1

Nov 06, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The BMPR2 c.1156G>C variant is a missense variant predicted to cause a glutamic acid to glutamine substitution at amino acid position 386. The variant is absent from the gnomAD v2.1.1 control and v4.1.0 populations (PM2_supporting). Only one patient with the variant has been reported (PMID: 26387786), and therefore, PS4 is not met. Glu386Gln is located in the catalytic kinase domain and is known to be an indispensable residue (PM1_strong). Other likely pathogenic missense variants causing a different amino acid change at the same residue have been reported, including Glu386Lys, Glu386Ala, Glu386Val, and Glu386Gly (PM5_supporting). Computational evidence for pathogenicity included a REVEL score of 0.961, which meets the threshold of >0.75 defined by the ClinGen Pulmonary Hypertension VCEP, and AlphaMissense 0.9837 (PP3 met but not BP4). Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation evidence. Similarly, functional data is unavailable for this variant, so BS3 and PS3 were not evaluated. In summary, this variant meets the criteria to be classified as likely pathogenic (LP) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_strong, PM2_supporting, PM5_supporting, and PP3 (VCEP specification version 1.1, 1/18/2024). -

Primary pulmonary hypertension Pathogenic:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 386 of the BMPR2 protein (p.Glu386Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pulmonary hypertension (PMID: 18503968; internal data). ClinVar contains an entry for this variant (Variation ID: 425884). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BMPR2 protein function with a positive predictive value of 95%. This variant disrupts the p.Glu386 amino acid residue in BMPR2. Other variant(s) that disrupt this residue have been observed in individuals with BMPR2-related conditions (PMID: 15591269, 18364108, 23675998), 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	0.98
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.9	D;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0080	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.96		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;
MVP		1.0
MPC		1.1
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs1085307306; hg19: chr2-203397335;