VCV000136528.31 - ClinVar

NM_001204.7(BMPR2):c.2324G>A (p.Ser775Asn)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001204.7(BMPR2):c.2324G>A (p.Ser775Asn)

Variation ID: 136528 Accession: VCV000136528.31

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q33.2 2: 202555989 (GRCh38) [ NCBI UCSC ] 2: 203420712 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 31, 2016	Sep 29, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001204.7:c.2324G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001195.2:p.Ser775Asn	missense
NC_000002.12:g.202555989G>A
NC_000002.11:g.203420712G>A
NG_009363.1:g.184663G>A
LRG_712:g.184663G>A
LRG_712t1:c.2324G>A
	Q13873:p.Ser775Asn

... more HGVS ... less HGVS

Protein change

S775N

Other names

p.S775N:AGC>AAC

Canonical SPDI

NC_000002.12:202555988:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00998 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.02516

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.02568

1000 Genomes Project 30x 0.00968

1000 Genomes Project 0.00998

Trans-Omics for Precision Medicine (TOPMed) 0.02229

The Genome Aggregation Database (gnomAD) 0.02286

The Genome Aggregation Database (gnomAD), exomes 0.02444

Links

ClinGen: CA295462 UniProtKB: Q13873#VAR_019996 dbSNP: rs2228545 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BMPR2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1091	1154

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign (5)	criteria provided, multiple submitters, no conflicts	Sep 3, 2015	RCV000150193.24
Pulmonary hypertension, primary, 1	Benign (1)	criteria provided, single submitter	Mar 6, 2018	RCV000332495.16
Primary pulmonary hypertension	Benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV001507246.15
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Nov 29, 2023	RCV001572744.18

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000307042.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Mar 27, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000167205.12 First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Oct 02, 2014)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000197114.4 First in ClinVar: Jan 30, 2015 Last updated: Oct 02, 2016	Publications: PubMed (9) PubMed: 20096498‚ 21070126‚ 22995991‚ 21228398‚ 19844076‚ 24936649‚ 16429395‚ 18503968‚ 16717148 Comment: p.Ser775Asn in exon 12 of BMPR2: This variant is not expected to have clinical s ignificance because it has been identified in 3.5% (301/8600) of … (more) p.Ser775Asn in exon 12 of BMPR2: This variant is not expected to have clinical s ignificance because it has been identified in 3.5% (301/8600) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs2228545). In addition, serine (Ser) is not conserved in mammals or evolutionarily distant species and the change to asparagine (Asn) is present in 5 mammals. (less) Number of individuals with the variant: 8
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Pulmonary hypertension, primary, 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000426393.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005240285.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Sep 03, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000257838.5 First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Primary pulmonary hypertension Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000560772.7 First in ClinVar: Dec 06, 2016 Last updated: Feb 20, 2024
Benign (Nov 29, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602652.7 First in ClinVar: Oct 02, 2016 Last updated: Feb 20, 2024
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001797574.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001920851.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

p.Ser775Asn in exon 12 of BMPR2: This variant is not expected to have clinical s ignificance because it has been identified in 3.5% (301/8600) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs2228545). In addition, serine (Ser) is not conserved in mammals or evolutionarily distant species and the change to asparagine (Asn) is present in 5 mammals.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel mutations in BMPR2, ACVRL1 and KCNA5 genes and hemodynamic parameters in patients with pulmonary arterial hypertension.	Pousada G	PloS one	2014	PMID: 24936649
An informatics approach to analyzing the incidentalome.	Berg JS	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22995991
Carrier testing for severe childhood recessive diseases by next-generation sequencing.	Bell CJ	Science translational medicine	2011	PMID: 21228398
A novel BMPR2 gene mutation associated with exercise-induced pulmonary hypertension in septal defects.	Möller T	Scandinavian cardiovascular journal : SCJ	2010	PMID: 21070126
[Study of the BMPR2 gene in patients with pulmonary arterial hypertension].	Portillo K	Archivos de bronconeumologia	2010	PMID: 20096498
Sequence variants in BMPR2 and genes involved in the serotonin and nitric oxide pathways in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: relation to clinical parameters and comparison with left heart disease.	Ulrich S	Respiration; international review of thoracic diseases	2010	PMID: 19844076
Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension.	Rosenzweig EB	The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation	2008	PMID: 18503968
Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension.	Elliott CG	Circulation	2006	PMID: 16717148
Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension.	Machado RD	Human mutation	2006	PMID: 16429395

Text-mined citations for rs2228545 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_001204.7(BMPR2):c.2324G>A (p.Ser775Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2228545 ...