ClinVar Genomic variation as it relates to human health
NM_001204.7(BMPR2):c.994C>T (p.Arg332Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001204.7(BMPR2):c.994C>T (p.Arg332Ter)
Variation ID: 8810 Accession: VCV000008810.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q33.2 2: 202530820 (GRCh38) [ NCBI UCSC ] 2: 203395543 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 Feb 14, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001204.7:c.994C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001195.2:p.Arg332Ter nonsense NC_000002.12:g.202530820C>T NC_000002.11:g.203395543C>T NG_009363.1:g.159494C>T LRG_712:g.159494C>T LRG_712t1:c.994C>T LRG_712p1:p.Arg332Ter - Protein change
- R332*
- Other names
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- Canonical SPDI
- NC_000002.12:202530819:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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BMPR2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1074 | 1137 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
no assertion criteria provided
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Jan 1, 2001 | RCV000009355.15 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 4, 2019 | RCV000498671.15 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001003704.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 28, 2024 | RCV001376626.12 |
Submissions - Germline
Classification
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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
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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
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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
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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. |
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Pathogenic
(Sep 04, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001156676.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 26, 2021 |
Comment:
The BMPR2 c.994C>T; p.Arg332Ter variant (rs137852751) is reported in the literature in multiple individuals affected with pulmonary arterial hypertension (Elliott 2006, Ghinga 2016, Machado 2001, … (more)
The BMPR2 c.994C>T; p.Arg332Ter variant (rs137852751) is reported in the literature in multiple individuals affected with pulmonary arterial hypertension (Elliott 2006, Ghinga 2016, Machado 2001, Sankelo 2005, Thomson 2000, Yang 2018). In two reports, this variant was also observed in several asymptomatic relatives of affected individuals, suggesting it may be incompletely penetrant (Machado 2001, Thomson 2000). The p.Arg332Ter variant is absent from general population databases (Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by several laboratories in ClinVar (Variation ID: 8810). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Arg332Ter variant is considered to be pathogenic. References Elliott CG et al. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation. 2006 May 30;113(21):2509-15. Ghigna MR et al. BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension. Eur Respir J. 2016 Dec;48(6):1668-1681. Machado RD et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet. 2001 Jan;68(1):92-102. Sankelo M et al. BMPR2 mutations have short lifetime expectancy in primary pulmonary hypertension. Hum Mutat. 2005 Aug;26(2):119-24. Thomson JR et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2000 Oct;37(10):741-5. Yang H et al. Genetic analyses in a cohort of 191 pulmonary arterial hypertension patients. Respir Res. 2018 May 9;19(1):87. (less)
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Pathogenic
(Jan 07, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000589545.3
First in ClinVar: Aug 20, 2017 Last updated: Apr 17, 2019 |
Comment:
The R332X variant in the BMPR2 gene has been reported in multiple probands with either familial or sporadic pulmonary hypertension (Thomson et al., 2000; Sankelo … (more)
The R332X variant in the BMPR2 gene has been reported in multiple probands with either familial or sporadic pulmonary hypertension (Thomson et al., 2000; Sankelo et al., 2005; Rosenzweig et al., 2008; Portillo et al., 2010; Ghigna et al., 2016; Yang et al., 2018) and this variant segregated with disease in at least one family (Machado et al., 2001). Reduced penetrance has also been observed (Thomson et al., 2000; Machado et al., 2001). The R332X variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other downstream nonsense variants in the BMPR2 gene have been reported in the Human Gene Mutation Database in association with PAH (Stenson et al., 2014), indicating that loss of function is an established disease mechanism. In addition, this variant is not observed in large population cohorts (Lek et al., 2016). (less)
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Pathogenic
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Primary pulmonary hypertension
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001235977.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg332*) in the BMPR2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg332*) in the BMPR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BMPR2 are known to be pathogenic (PMID: 16429395). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with pulmonary arterial hypertension (PMID: 11015450, 30578397). ClinVar contains an entry for this variant (Variation ID: 8810). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2001)
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no assertion criteria provided
Method: literature only
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PULMONARY HYPERTENSION, PRIMARY, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029573.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 apparently unrelated families, Machado et al. (2001) found that multiple members affected by primary pulmonary hypertension (PPH1; 178600) carried a C-to-T transition at … (more)
In 2 apparently unrelated families, Machado et al. (2001) found that multiple members affected by primary pulmonary hypertension (PPH1; 178600) carried a C-to-T transition at nucleotide 994 of the BMPR2 gene, resulting in an arg332-to-ter mutation. In one family, a parent and child were affected, with onset at 28 and 32 years of age; in the other family, 8 members of 3 generations were affected with an age of onset ranging from 13 to 42 years. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: literature only
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Primary pulmonary hypertension
Affected status: yes
Allele origin:
germline
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Rare Disease Genomics Group, St George's University of London
Accession: SCV000576150.1
First in ClinVar: May 13, 2017 Last updated: May 13, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Pulmonary arterial hypertension
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162147.1
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
Observation 3:
Number of individuals with the variant: 1
Sex: male
Observation 4:
Number of individuals with the variant: 1
Sex: male
Observation 5:
Number of individuals with the variant: 1
Sex: female
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension. | Wang XJ | The European respiratory journal | 2019 | PMID: 30578397 |
Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. | Machado RD | Human mutation | 2015 | PMID: 26387786 |
Molecular genetics and clinical features of Chinese idiopathic and heritable pulmonary arterial hypertension patients. | Liu D | The European respiratory journal | 2012 | PMID: 21737554 |
Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension. | Girerd B | Respiratory research | 2010 | PMID: 20534176 |
[Study of the BMPR2 gene in patients with pulmonary arterial hypertension]. | Portillo K | Archivos de bronconeumologia | 2010 | PMID: 20096498 |
Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. | Elliott CG | Circulation | 2006 | PMID: 16717148 |
Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. | Machado RD | Human mutation | 2006 | PMID: 16429395 |
BMPR2 mutations have short lifetime expectancy in primary pulmonary hypertension. | Sankelo M | Human mutation | 2005 | PMID: 15965979 |
BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. | Machado RD | American journal of human genetics | 2001 | PMID: 11115378 |
Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. | Thomson JR | Journal of medical genetics | 2000 | PMID: 11015450 |
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Text-mined citations for rs137852751 ...
HelpRecord last updated May 12, 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.