ClinVar Miner

Submissions for variant NM_001204.7(BMPR2):c.1771C>T (p.Arg591Ter)

gnomAD frequency: 0.00001  dbSNP: rs777458559
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000488717 SCV002767312 pathogenic Pulmonary hypertension, primary, 1 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with BMPR2-related pulmonary hypertension (MIM#178600) and pulmonary venoocclusive disease 1 (MIM#265450). Dominant negative is also a suggested mechanism of disease (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 33380512). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic, and have been observed in individuals with pulmonary arterial hypertension (PAH) (Decipher, PMID: 26387786). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic (ClinVar, LOVD) and has been observed in at least one family with PAH (PMID: 26387786, PMID: 18356561). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV003315244 SCV004014871 likely pathogenic BMPR2-related disorders criteria provided, single submitter clinical testing This nonsense variant found in exon 12 of 13 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in BMPR2 is an established mechanism of disease (PMID: 36603064). This variant has been previously reported as a heterozygous change in patients with BMPR2-related disorders (PMID: 18356561, 25429696, 26387786). The c.1771C>T (p.Arg591Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/282746) and thus is presumed to be rare. Based on the available evidence, c.1771C>T (p.Arg591Ter) is classified as Likely Pathogenic.
Rare Disease Genomics Group, St George's University of London RCV000488717 SCV000576268 pathogenic Pulmonary hypertension, primary, 1 no assertion criteria provided literature only

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