Submissions for variant NM_001204.7(BMPR2):c.545G>A (p.Gly182Asp)

gnomAD frequency: 0.00016  dbSNP: rs137852754

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen	RCV004549351	SCV005043316	likely benign	Pulmonary arterial hypertension	2024-05-03	reviewed by expert panel	curation	The NM_0001204.7(BMPR2) c.545G>A variant is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 182 (p.Gly182Asp). The highest subpopulation minor allele frequency in gnomAD v2.1.1 (controls) is 0.0003507 in the European (non-Finnish) population, which is higher than the ClinGen PH VCEP threshold (<0.01%) for PM2 but lower than the threshold (>0.1%) for BS1. Therefore, this variant does not meet either of these population criteria. The REVEL computational prediction analysis tool produced a score of 0.8069, which is above the threshold (>0.75) for pathogenicity (PP3). Luciferase assay data indicated that variant transcriptional activity was comparable to wild-type, indicating no deleterious effect (BS3; PMID: 18321866). The PH Expert Panel reviewed the conflicting evidence (PP3) and felt it did not override the Likely Benign classification in this case. In summary, this variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS3, PP3. (VCEP specifications version 1.1, 1/18/2024)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508281	SCV000602650	uncertain significance	not provided	2018-03-23	criteria provided, single submitter	clinical testing	The BMPR2 c.545G>A; p.Gly182Asp variant (rs137852754) has been previously identified in a patient diagnosed with fenfluramine-associated primary pulmonary hypertension (PAH) after taking the drug for 2 months (Humbert 2002). It is reported in ClinVar (Variation ID: 8813) and is observed in the non-Finnish European population at an overall frequency of 0.03% (38/126718 alleles) in the Genome Aggregation Database. The glycine at codon 182 is highly conserved but computational algorithms (SIFT: tolerated, PolyPhen2: damaging) predict conflicting effects of this variant on protein structure/function. Functional studies have suggested that the variant protein induces a transcriptional response following BMP4 stimulation in a manner indistinguishable from wild type BMPR2, although statistical analyses supporting this conclusion were not performed (Nasim 2008). Due to incomplete and conflicting information, the clinical significance of this variant cannot be determined with certainty. References: Humbert et al. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J. 2002; 20(3): 518-523. Nasim et al. Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Hum Mol Genet. 2008; 17(11): 1683-1694.
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735374	SCV000854528	uncertain significance	Seizure; Micrognathia; Cognitive impairment; Cafe-au-lait spot; Frontal bossing; High forehead; Abnormal basal ganglia morphology; Thoracic scoliosis; Abnormal basal ganglia MRI signal intensity		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272013	SCV002557383	uncertain significance	Pulmonary hypertension, primary, 1	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_001204.6(BMPR2):c.545G>A in exon 5 of 13 of the BMPR2 gene. This substitution is predicted to create a moderate amino acid change from glycine to aspartic acid at position 182 of the protein, NP_001195.2(BMPR2):p.(Gly182Asp). The glycine at this position has very high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predicts this variant to be pathogenic (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a frequency of 0.014% (39 heterozygotes; 0 homozygotes). The variant has been previously reported in a patient with pulmonary hypertension and also described as a VUS (ClinVar, Humbert, M. et al. (2002)). In addition, functional studies of the variant showed that transcriptional activities were comparable to wild-type (Nasim, M. et al. (2008)). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512940	SCV002989740	likely benign	Primary pulmonary hypertension	2023-11-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000508281	SCV004183858	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	BMPR2: PM2:Supporting, PP3
OMIM	RCV000009359	SCV000029577	pathogenic	Pulmonary hypertension, primary, fenfluramine-associated	2002-09-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000508281	SCV001552623	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BMPR2 p.Gly182Asp variant was identified in one individual with fenfluramine-associated pulmonary hypertension (Humbert_2002_PMID:12358323). Functional analysis revealed no difference in BMPR2 protein activity with the p.Gly182Asp variant compared to wild type (Nasim_ 2008_PMID:18321866). The variant was identified in dbSNP (ID: rs137852754), ClinVar (classified as uncertain significance by ARUP Laboratories and CHLA Center for Personalized Medicine), and LOVD 3.0 (variant effect not shared). The variant was identified in control databases in 39 of 282854 chromosomes at a frequency of 0.0001379 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 39 of 129172 chromosomes (freq: 0.000302), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Gly182 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.