rs1085307216

Variant names:

• chr2-202467624-G-A
• rs1085307216
• NM_001204.7:c.353G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_001204.7(BMPR2):​c.353G>A​(p.Cys118Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C118W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 8.26
• Publications: 4 publications found

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]

BMPR2 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pulmonary hypertension, primary, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001204.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-202467625-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 8799.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 2-202467624-G-A is Pathogenic according to our data. Variant chr2-202467624-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 425768.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.353G>A	p.Cys118Tyr	missense_variant	Exon 3 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.353G>A	p.Cys118Tyr	missense_variant	Exon 3 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.353G>A	p.Cys118Tyr	missense_variant	Exon 3 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.353G>A	p.Cys118Tyr	missense_variant	Exon 3 of 12	2		ENSP00000363702.2
BMPR2	ENST00000479069.1	n.260G>A		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 04, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BMPR2 c.353G>A; p.Cys118Tyr variant (rs1085307216) is reported in the literature in several individuals affected with pulmonary arterial hypertension (PAH) (Machado 2006, Pfarr 2011). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 118 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Other amino acid substitutions at this codon and the adjacent cysteine (p.Cys117Tyr, p.Cys118Trp, p.Cys118Ser) have been reported in individuals with PAH and are considered disease-causing (Barozzi 2019, Machado 2006). Further, functional assays indicate that several of these other substitutions (p.Cys117Tyr and p.Cys118Trp) are mislocalized in the cell and exhibit signaling defects (Rudarakanchana 2002, Sobolewski 2008). Based on available information, the p.Cys118Tyr variant is considered to be likely pathogenic. References: Barozzi C et al. A Combined Targeted and Whole Exome Sequencing Approach Identified Novel Candidate Genes Involved in Heritable Pulmonary Arterial Hypertension. Sci Rep. 2019 Jan 24;9(1):753. Machado RD et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat. 2006 Feb;27(2):121-32. Pfarr N et al. Hemodynamic and clinical onset in patients with hereditary pulmonary arterial hypertension and BMPR2 mutations. Respir Res. 2011 Jul 29;12:99. Rudarakanchana N et al. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet. 2002 Jun 15;11(13):1517-25. Sobolewski A et al. Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue. Hum Mol Genet. 2008 Oct 15;17(20):3180-90. -

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

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Pulmonary arterial hypertension;C5679820:Idiopathic and/or familial pulmonary arterial hypertension Other:1

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Wendy Chung Laboratory, Boston Children's Hospital

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	2.9	M;M;.
PhyloP100		8.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-11	D;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.97		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		5.4
Varity_R		1.0
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1085307216; hg19: chr2-203332347;