Submissions for variant NM_001204.7(BMPR2):c.276A>C (p.Gln92His)

gnomAD frequency: 0.00001  dbSNP: rs140683387

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen	RCV004777621	SCV005393838	likely benign	Pulmonary arterial hypertension	2024-11-01	reviewed by expert panel	curation	The BMPR2 c.276A>C variant is a missense variant predicted to cause substitution of glutamine to histidine at amino acid position 92 (p.(Gln92His)). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.001589 in the East Asian population (Korean) (BS1 met but not PM2 or BA1). Computational predictor REVEL score is 0.57, which is in between the PH-VCEP specified threshold of ≤0.25 and ≥0.75, so neither PP3 nor BP4 are met. This variant is located in the extracellular domain, critical for ligand binding (PM1 met), but does not affect a known critical or non-critical amino acid (no up- or downward adjustment for PM1). BS2 was not met due to absence of homozygous individuals (gnomAD v.2.1.1 controls). PS4 was not applied as PM2 was not met. PP1, PS2, PM6 were not met due to the absence of co-segregation data. PS3 and BS3 were not met due to the lack of experimental evidence. Although other variants in the same amino acid been reported, for pulmonary arterial hypertension, the variants were not deemed pathogenic or likely pathogenic by the PH-VCEP (PS1, PM5 not met). 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: BS1, PM1 (VCEP specification version 1.1.0, 1/18/2024).
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000488455	SCV000267228	uncertain significance	Pulmonary hypertension, primary, 1	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV001753635	SCV001985398	uncertain significance	not provided	2020-06-19	criteria provided, single submitter	clinical testing	Present in two Japanese patients reported to have pulmonary arterial hypertension and in a patient with anomalous unilateral single pulmonary vein (Kabata et al., 2013; Koyama et al., 2014; Kobayashi et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29718794, 24583436, 23675998, 27002414)
Fulgent Genetics, Fulgent Genetics	RCV002494550	SCV002780849	uncertain significance	Pulmonary hypertension, primary, 1; Pulmonary venoocclusive disease 1	2021-11-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517440	SCV003517063	benign	Primary pulmonary hypertension	2024-01-25	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001753635	SCV005408989	uncertain significance	not provided	2024-03-11	criteria provided, single submitter	clinical testing	BP5
Rare Disease Genomics Group, St George's University of London	RCV000488455	SCV000576023	uncertain significance	Pulmonary hypertension, primary, 1		no assertion criteria provided	literature only