rs200948870

Positions:

• chr2-202520142-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS3 PM1

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.908G>A variant is a missense variant in exon 7 predicted to result in substitution of arginine to histidine at amino acid position 303 (p. Arg303His). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.00043 (1/2334 alleles) in subpopulation “remaining individuals” which exceeds the ClinGen PH VCEP threshold (<0.01%) for PM2 (PM2 not met). Neither BS1 (≥0.1%) nor BA1 (1%) met. The computational predictor REVEL gives a score of 0.497 indicating neither PP3 (≥0.75) nor BP4 (≤0.25) met. SpliceAI algorithm predicts no deleterious effect on acceptor or donor splice site. The variant is located in the kinase domain (PM1 met). Genetic evidence showed the presence of the variant in only one IPAH patient (PMID:16429395) (PS4 not met). Immunofluorescence staining of Hela cells transfected with an R303H mutant construct showed mislocalization of BMPR2 protein to the endoplasmic reticulum (PMID:25688877) and included positive and negative controls (PS3 met). In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PM1 (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2061247/MONDO:0015924/125

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:3
• Conservation: PhyloP100: 7.47

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 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMPR2	NM_001204.7	c.908G>A	p.Arg303His	missense_variant	7/13	ENST00000374580.10
BMPR2	XM_011511687.2	c.908G>A	p.Arg303His	missense_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMPR2	ENST00000374580.10	c.908G>A	p.Arg303His	missense_variant	7/13	1	NM_001204.7	P1
BMPR2	ENST00000374574.2	c.908G>A	p.Arg303His	missense_variant	7/12	2

Frequencies

GnomAD3 genomes AF: 0.0000531 AC: 8 AN: 150672 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251372 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135874

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461728 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727158

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000531 AC: 8 AN: 150790 Hom.: 0 Cov.: 32 AF XY: 0.0000816 AC XY: 6 AN XY: 73496

Gnomad4 AFR AF: 0.0000488

Gnomad4 AMR AF: 0.0000665

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000616 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary hypertension, primary, 1 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	Rare Disease Genomics Group, St George's University of London	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial primary pulmonary hypertension 1, with or without HHT (MIM#178600), primary fenfluramine or dexfenfluramine-associated pulmonary hypertension (MIM#178600) and pulmonary venoocclusive disease 1 (MIM#265450). However, gain of function has been noted in relation to upregulation of p38 MAPK-dependent pro-proliferative pathways and dominant negative has also been suggested as a mechanism in relation to SMAD signalling (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been reported for pulmonary arterial hypertension (PMID: 33380512). (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Arg303Cys): 2 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated protein kinase domain (UniProt). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg303Cys) variant has been reported in one individual with congenital heart disease and pulmonary arterial hypertension (PMID: 27002414). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported in one individual with pulmonary arterial hypertension (PMID: 16429395). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs carrying the p.(Arg303His) variant were retained in the endoplasmic reticulum compared to WT constructs that were localised to the plasma membrane. Additionally, mutant protein also demonstrated incomplete post-translational modification compared to WT protein (PMID: 25688877). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Pulmonary arterial hypertension Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Sep 10, 2024

The BMPR2 c.908G>A variant is a missense variant in exon 7 predicted to result in substitution of arginine to histidine at amino acid position 303 (p. Arg303His). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.00043 (1/2334 alleles) in subpopulation “remaining individuals” which exceeds the ClinGen PH VCEP threshold (<0.01%) for PM2 (PM2 not met). Neither BS1 (≥0.1%) nor BA1 (1%) met. The computational predictor REVEL gives a score of 0.497 indicating neither PP3 (≥0.75) nor BP4 (≤0.25) met. SpliceAI algorithm predicts no deleterious effect on acceptor or donor splice site. The variant is located in the kinase domain (PM1 met). Genetic evidence showed the presence of the variant in only one IPAH patient (PMID:16429395) (PS4 not met). Immunofluorescence staining of Hela cells transfected with an R303H mutant construct showed mislocalization of BMPR2 protein to the endoplasmic reticulum (PMID:25688877) and included positive and negative controls (PS3 met). In summary, the variant meets the criteria to be classified as likely pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS3, PM1 (VCEP specification version 1.1, 1/18/2024). -

Pulmonary venoocclusive disease 1;C4552070:Pulmonary hypertension, primary, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 19, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Jan 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;.;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.0	N;N;.
REVEL	Uncertain	0.50
Sift	Benign	0.10	T;D;.
Sift4G	Benign	0.15	T;T;.
Polyphen		1.0	D;.;.
Vest4		0.93
MVP		0.91
MPC		1.1
ClinPred		0.37	T
GERP RS		5.0
Varity_R		0.47
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200948870; hg19: chr2-203384865; COSMIC: COSV65813036; COSMIC: COSV65813036;