rs1085307312

Variant names:

• chr2-202532658-T-C
• rs1085307312
• NM_001204.7:c.1202T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1202T>C (p.Leu401Ser) variant is a missense variant harboured inexon 9 of the BMPR2 gene, predicted to cause substitution of leucine toserine encoding the functionally relevant catalytic kinase domain but withoutfunctional evidence indicating either critical or non-critical amino acid residue (PM1_moderate). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.72, below the PH VCEP threshold of >=0.75 for pathogenicity but above the threshold of <=0.25 for benignity (PP3 and BP4 not met). The variant has been identified in a single individual with hereditary PAH, included in two reports (PMID:32581362 and PMID:16429395) (PS4 not met). The variant was paternally inherited (PS2 not met). Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting, PP3_not met (VCEP specification version 1.1.0, 1/18/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA350341841/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 31)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 7.73

Genes affected

BMPR2 (HGNC:1078): (bone morphogenetic protein receptor type 2) This gene encodes a member of the bone morphogenetic protein (BMP) receptor family of transmembrane serine/threonine kinases. The ligands of this receptor are members of the TGF-beta superfamily. BMPs are involved in endochondral bone formation and embryogenesis. These proteins transduce their signals through the formation of heteromeric complexes of two different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Mutations in this gene have been associated with primary pulmonary hypertension, both familial and fenfluramine-associated, and with pulmonary venoocclusive disease. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.1202T>C	p.Leu401Ser	missense_variant	Exon 9 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.1202T>C	p.Leu401Ser	missense_variant	Exon 9 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.1202T>C	p.Leu401Ser	missense_variant	Exon 9 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.1202T>C	p.Leu401Ser	missense_variant	Exon 9 of 12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension Pathogenic:1 Uncertain:1

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NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 03, 2025

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.1202T>C (p.Leu401Ser) variant is a missense variant harboured in exon 9 of the BMPR2 gene, predicted to cause substitution of leucine to serine encoding the functionally relevant catalytic kinase domain but without functional evidence indicating either critical or non-critical amino acid residue (PM1_moderate). This variant is absent from gnomAD v2.1.1 (controls) and v4.1 (PM2_supporting). The REVEL prediction algorithm score is 0.72, below the PH VCEP threshold of >=0.75 for pathogenicity but above the threshold of <=0.25 for benignity (PP3 and BP4 not met). The variant has been identified in a single individual with hereditary PAH, included in two reports (PMID: 32581362 and PMID: 16429395) (PS4 not met). The variant was paternally inherited (PS2 not met). Functional studies have not been conducted for this variant (PS3 not assessed). In summary, this variant meets the criteria to be classified as a variant of unknown significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM1_moderate, PM2_supporting, PP3_not met (VCEP specification version 1.1.0, 1/18/2024) -

Pulmonary hypertension, primary, 1 Pathogenic:1

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Rare Disease Genomics Group, St George's University of London

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.56	N;N;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D;D;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.84
MutPred		0.85		Gain of disorder (P = 0.0045);Gain of disorder (P = 0.0045);.;
MVP		0.93
MPC		1.3
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1085307312; hg19: chr2-203397381;