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NM_001204.7(BMPR2):c.968-5A>G AND Pulmonary arterial hypertension

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 3, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV004551530.1

Allele description [Variation Report for NM_001204.7(BMPR2):c.968-5A>G]

NM_001204.7(BMPR2):c.968-5A>G

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.968-5A>G
HGVS:
  • NC_000002.12:g.202530789A>G
  • NG_009363.1:g.159463A>G
  • NM_001204.7:c.968-5A>GMANE SELECT
  • LRG_712t1:c.968-5A>G
  • LRG_712:g.159463A>G
  • NC_000002.11:g.203395512A>G
  • NM_001204.6:c.968-5A>G
Links:
dbSNP: rs1060502584
NCBI 1000 Genomes Browser:
rs1060502584
Molecular consequence:
  • NM_001204.7:c.968-5A>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Pulmonary arterial hypertension
Identifiers:
MONDO: MONDO:0015924; MeSH: D000081029; MedGen: C2973725; Orphanet: 182090; Human Phenotype Ontology: HP:0002092

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005043300Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen PH ACMG Specifications BMPR2 V1.1.0)		Pathogenic
(May 3, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen, SCV005043300.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_001204.7(BMPR2) c.968-5A>G is an intronic variant at Intron 7. This variant is absent from gnomAD v2.1.1 and v3.1.2 controls (PM2_supporting). It is predicted to create a strong acceptor site gain (PP3_supporting) and PH VCEP internal unpublished RNA sequencing data confirmed an effect on splicing leading to NMD. The c.968-5G>A variant leads to the inclusion of 4 bases of intron 7 into the mature mRNA creating a frameshift and a STOP codon at position 327(PVS1_strong). The variant has been reported in 2 unrelated PAH patients: first proband is associated with the publication (PMID: 19555857) and the second proband, with no further information for co-segregation, is from an internal lab contributor (PS4_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PVS1_strong, PM2_supporting, PS4_supporting and PP3_supporting (VCEP specifications version 1.1, 1/18/2024)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024