This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 491 of the BMPR2 protein (p.Arg491Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pulmonary hypertension (PMID: 10903931, 28388887). ClinVar contains an entry for this variant (Variation ID: 8802). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg491 amino acid residue in BMPR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001204.7(BMPR2):c.1471C>T (p.Arg491Trp)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001204.7(BMPR2):c.1471C>T (p.Arg491Trp)
Variation ID: 8802 Accession: VCV000008802.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q33.2 2: 202552773 (GRCh38) [ NCBI UCSC ] 2: 203417496 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 2, 2016 Oct 8, 2024 Dec 30, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001204.7:c.1471C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001195.2:p.Arg491Trp missense NC_000002.12:g.202552773C>T NC_000002.11:g.203417496C>T NG_009363.1:g.181447C>T LRG_712:g.181447C>T LRG_712t1:c.1471C>T LRG_712p1:p.Arg491Trp Q13873:p.Arg491Trp - Protein change
- R491W
- Other names
- -
- Canonical SPDI
- NC_000002.12:202552772:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BMPR2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1091 | 1154 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
no assertion criteria provided
|
Jul 11, 2016 | RCV000009347.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 11, 2023 | RCV000493405.4 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Sep 26, 2022 | RCV001003725.3 | |
| not provided (1) |
no classification provided
|
- | RCV001823867.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 30, 2023 | RCV002512939.4 | |
|
BMPR2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Mar 21, 2024 | RCV004549350.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pulmonary arterial hypertension
Affected status: unknown
Allele origin:
germline
|
John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine
Accession: SCV002575048.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
|
|
|
Pathogenic
(Dec 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary pulmonary hypertension
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003524968.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 491 of the BMPR2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 491 of the BMPR2 protein (p.Arg491Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pulmonary hypertension (PMID: 10903931, 28388887). ClinVar contains an entry for this variant (Variation ID: 8802). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg491 amino acid residue in BMPR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582363.5
First in ClinVar: Jul 02, 2017 Last updated: Apr 23, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant inhibits Smad pathway activation and leads to disruption … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant inhibits Smad pathway activation and leads to disruption of other downstream signalling pathways (Rudarakanchana et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27587546, 21737554, 32634488, 35346192, 32581362, 19324947, 25688877, 27811071, 29843651, 28388887, 29743074, 30578397, 26387786, 14985116, 20002458, 15591269, 16429395, 11502704, 12045205, 20534176, 18356561, 15059534, 16002577, 10903931, 18503968, 31727138, 32966279, 33066286, 21801371) (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: literature only
|
Primary pulmonary hypertension
Affected status: yes
Allele origin:
germline
|
Rare Disease Genomics Group, St George's University of London
Accession: SCV000576249.1
First in ClinVar: May 13, 2017 Last updated: May 13, 2017 |
|
|
|
Pathogenic
(Sep 01, 2000)
|
no assertion criteria provided
Method: literature only
|
PULMONARY HYPERTENSION, PRIMARY, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029565.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 23, 2018 |
Comment on evidence:
In a family with primary pulmonary hypertension (PPH1; 178600), Deng et al. (2000) reported a C-to-T transition at position 1471 in exon 11 of the … (more)
In a family with primary pulmonary hypertension (PPH1; 178600), Deng et al. (2000) reported a C-to-T transition at position 1471 in exon 11 of the BMPR2 gene that was predicted to result in an arg491-to-trp (R491W) substitution. This amino acid substitution occurs at an arginine that is highly conserved in all type II TGF-beta receptors and appears to be homologous to the invariant arg280 in subdomain XI in other protein kinases (Hanks et al., 1988). (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Pulmonary arterial hypertension
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162168.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Observation 2:
Number of individuals with the variant: 1
Sex: female
Observation 3:
Number of individuals with the variant: 1
Sex: female
Observation 4:
Number of individuals with the variant: 1
Sex: male
Observation 5:
Number of individuals with the variant: 1
Observation 6:
Number of individuals with the variant: 1
Sex: female
|
|
|
Pathogenic
(Mar 21, 2024)
|
no assertion criteria provided
Method: clinical testing
|
BMPR2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004109284.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The BMPR2 c.1471C>T variant is predicted to result in the amino acid substitution p.Arg491Trp. This variant has been reported in patients with pulmonary arterial hypertension … (more)
The BMPR2 c.1471C>T variant is predicted to result in the amino acid substitution p.Arg491Trp. This variant has been reported in patients with pulmonary arterial hypertension (PAH) (e.g., Liu et al. 2011. PubMed ID: 21737554; Ghigna et al. 2016. PubMed ID: 27811071; Yang et al. 2018. PubMed ID: 29743074; Wang et al. 2019. PubMed ID: 30578397, see Supplementary Dataset 1). An alternate substitution of the same amino acid (p.Arg491Gln) has also been reported in PAH patients (Liu et al. 2011. PubMed ID: 21737554). The p.Arg491 amino acid is located in the BMPR2 kinase domain, and alterations of this amino acid have been reported to disrupt downstream signaling (Rudarakanchana et al. 2002. PubMed ID: 12045205; Dewachter et al. 2009. PubMed ID: 19324947). This variant has not been reported in the literature or in a large population database, indicating it is rare. Several outside laboratories have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/8802/). This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Jul 11, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Pulmonary hypertension, primary, 1
Affected status: yes
Allele origin:
germline
|
Center for Genomic Medicine, Kyoto University Graduate School of Medicine
Accession: SCV000320702.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Pulmonary arterial hypertension
None
Affected status: yes
Allele origin:
germline
|
Wendy Chung Laboratory, Columbia University Medical Center
Accession: SCV002073643.1
First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022 |
Age: 40-49 years
Sex: female
Ethnicity/Population group: AFR
|
Comment:
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant inhibits Smad pathway activation and leads to disruption of other downstream signalling pathways (Rudarakanchana et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27587546, 21737554, 32634488, 35346192, 32581362, 19324947, 25688877, 27811071, 29843651, 28388887, 29743074, 30578397, 26387786, 14985116, 20002458, 15591269, 16429395, 11502704, 12045205, 20534176, 18356561, 15059534, 16002577, 10903931, 18503968, 31727138, 32966279, 33066286, 21801371)
Comment:
The BMPR2 c.1471C>T variant is predicted to result in the amino acid substitution p.Arg491Trp. This variant has been reported in patients with pulmonary arterial hypertension (PAH) (e.g., Liu et al. 2011. PubMed ID: 21737554; Ghigna et al. 2016. PubMed ID: 27811071; Yang et al. 2018. PubMed ID: 29743074; Wang et al. 2019. PubMed ID: 30578397, see Supplementary Dataset 1). An alternate substitution of the same amino acid (p.Arg491Gln) has also been reported in PAH patients (Liu et al. 2011. PubMed ID: 21737554). The p.Arg491 amino acid is located in the BMPR2 kinase domain, and alterations of this amino acid have been reported to disrupt downstream signaling (Rudarakanchana et al. 2002. PubMed ID: 12045205; Dewachter et al. 2009. PubMed ID: 19324947). This variant has not been reported in the literature or in a large population database, indicating it is rare. Several outside laboratories have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/8802/). This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 491 of the BMPR2 protein (p.Arg491Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pulmonary hypertension (PMID: 10903931, 28388887). ClinVar contains an entry for this variant (Variation ID: 8802). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg491 amino acid residue in BMPR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that this variant inhibits Smad pathway activation and leads to disruption of other downstream signalling pathways (Rudarakanchana et al., 2002); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27587546, 21737554, 32634488, 35346192, 32581362, 19324947, 25688877, 27811071, 29843651, 28388887, 29743074, 30578397, 26387786, 14985116, 20002458, 15591269, 16429395, 11502704, 12045205, 20534176, 18356561, 15059534, 16002577, 10903931, 18503968, 31727138, 32966279, 33066286, 21801371)
Comment:
The BMPR2 c.1471C>T variant is predicted to result in the amino acid substitution p.Arg491Trp. This variant has been reported in patients with pulmonary arterial hypertension (PAH) (e.g., Liu et al. 2011. PubMed ID: 21737554; Ghigna et al. 2016. PubMed ID: 27811071; Yang et al. 2018. PubMed ID: 29743074; Wang et al. 2019. PubMed ID: 30578397, see Supplementary Dataset 1). An alternate substitution of the same amino acid (p.Arg491Gln) has also been reported in PAH patients (Liu et al. 2011. PubMed ID: 21737554). The p.Arg491 amino acid is located in the BMPR2 kinase domain, and alterations of this amino acid have been reported to disrupt downstream signaling (Rudarakanchana et al. 2002. PubMed ID: 12045205; Dewachter et al. 2009. PubMed ID: 19324947). This variant has not been reported in the literature or in a large population database, indicating it is rare. Several outside laboratories have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/8802/). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
| Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension. | Zhu N | Genome medicine | 2019 | PMID: 31727138 |
| A burden of rare variants in BMPR2 and KCNK3 contributes to a risk of familial pulmonary arterial hypertension. | Higasa K | BMC pulmonary medicine | 2017 | PMID: 28388887 |
| Molecular genetics and clinical features of Chinese idiopathic and heritable pulmonary arterial hypertension patients. | Liu D | The European respiratory journal | 2012 | PMID: 21737554 |
| Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations. | Pfarr N | Respiratory research | 2011 | PMID: 21801371 |
| Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension. | Girerd B | Respiratory research | 2010 | PMID: 20534176 |
| Identities and frequencies of BMPR2 mutations in Chinese patients with idiopathic pulmonary arterial hypertension. | Wang H | Clinical genetics | 2010 | PMID: 20002458 |
| Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. | Machado RD | Human mutation | 2006 | PMID: 16429395 |
| Low frequency of BMPR2 mutations in a German cohort of patients with sporadic idiopathic pulmonary arterial hypertension. | Koehler R | Journal of medical genetics | 2004 | PMID: 15591269 |
| [Clinical and genetic characteristics of a Chinese family of primary pulmonary hypertension]. | Jing ZC | Zhonghua yi xue za zhi | 2004 | PMID: 15059534 |
| Bone morphogenetic protein receptor-II mutation Arg491Trp causes malignant phenotype of familial primary pulmonary hypertension. | Zhicheng J | Biochemical and biophysical research communications | 2004 | PMID: 14985116 |
| Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. | Morrell NW | Circulation | 2001 | PMID: 11502704 |
| Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. | Deng Z | American journal of human genetics | 2000 | PMID: 10903931 |
| The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. | Hanks SK | Science (New York, N.Y.) | 1988 | PMID: 3291115 |
| click to load more click to collapse | ||||
Text-mined citations for rs137852746 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.