NM_001204.7(BMPR2):c.994C>T (p.Arg332Ter) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 4, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000498671.15

Allele description [Variation Report for NM_001204.7(BMPR2):c.994C>T (p.Arg332Ter)]

NM_001204.7(BMPR2):c.994C>T (p.Arg332Ter)

Gene:

BMPR2:bone morphogenetic protein receptor type 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q33.2

Genomic location:

Preferred name:

NM_001204.7(BMPR2):c.994C>T (p.Arg332Ter)

HGVS:

NC_000002.12:g.202530820C>T
NG_009363.1:g.159494C>T
NM_001204.7:c.994C>TMANE SELECT
NP_001195.2:p.Arg332Ter
LRG_712t1:c.994C>T
LRG_712:g.159494C>T
LRG_712p1:p.Arg332Ter
NC_000002.11:g.203395543C>T
NM_001204.6:c.994C>T
NP_001195.2:p.R332*

Protein change:

R332*; ARG332TER

Links:

OMIM: 600799.0017; dbSNP: rs137852751

NCBI 1000 Genomes Browser:

rs137852751

Molecular consequence:

NM_001204.7:c.994C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000589545	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jan 7, 2019)	germline	clinical testing	Citation Link,
SCV001156676	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Sep 4, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000589545

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jan 7, 2019)

germline

clinical testing

Citation Link,

SCV001156676

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Sep 4, 2019)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000589545.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001156676.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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