ClinVar Miner

Submissions for variant NM_001204.7(BMPR2):c.545G>A (p.Gly182Asp) (rs137852754)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735374 SCV000854528 uncertain significance Seizures; Micrognathia; Cognitive impairment; Cafe-au-lait spot; Frontal bossing; High forehead; Abnormality of the basal ganglia; Thoracic scoliosis; Abnormal basal ganglia MRI signal intensity criteria provided, single submitter clinical testing
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.

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