VCV000498501.13 - ClinVar

NM_006129.5(BMP1):c.2134G>A (p.Gly712Ser)

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.

(6)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006129.5(BMP1):c.2134G>A (p.Gly712Ser)

Variation ID: 498501 Accession: VCV000498501.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8p21.3 8: 22201829 (GRCh38) [ NCBI UCSC ] 8: 22059342 (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	Apr 2, 2018	Nov 24, 2024	Jun 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006129.5:c.2134G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006120.1:p.Gly712Ser	missense
NR_033403.2:n.2205G>A		non-coding transcript variant
NC_000008.11:g.22201829G>A
NC_000008.10:g.22059342G>A
NG_029659.1:g.41690G>A

... more HGVS ... less HGVS

Protein change

G712S

Other names

p.Gly712Ser

Canonical SPDI

NC_000008.11:22201828: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.

0.00060 (A)

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

1000 Genomes Project 30x 0.00062

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062

The Genome Aggregation Database (gnomAD) 0.00064

The Genome Aggregation Database (gnomAD), exomes 0.00080

Exome Aggregation Consortium (ExAC) 0.00094

1000 Genomes Project 0.00060

Trans-Omics for Precision Medicine (TOPMed) 0.00061

Links

ClinGen: CA4665133 dbSNP: rs117159093 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.
BMP1		-	-	GRCh38 GRCh37	723	1017

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.
Osteogenesis imperfecta type 13	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 22, 2023	RCV001162110.5
not provided	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Jun 18, 2024	RCV000597608.9

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.
Uncertain significance (Dec 13, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000703544.2 First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BMP1 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Jun 19, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Osteogenesis imperfecta type 13 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001324045.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Jul 29, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002145687.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Comment: This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 712 of the BMP1 protein (p.Gly712Ser). … (more) This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 712 of the BMP1 protein (p.Gly712Ser). This variant is present in population databases (rs117159093, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with BMP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 498501). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (May 15, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003926147.1 First in ClinVar: May 27, 2023 Last updated: May 27, 2023	Comment: Reported in a patient with an atypical femur fracture, however a second BMP1 variant was not identified (Zhou et al., 2023); In silico analysis supports … (more) Reported in a patient with an atypical femur fracture, however a second BMP1 variant was not identified (Zhou et al., 2023); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37076969, PollitR2019[thesis]) (less)
Uncertain significance (Feb 22, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Osteogenesis imperfecta type 13 Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004562144.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Comment: The BMP1 c.2134G>A; p.Gly712Ser variant (rs117159093), to our knowledge, is not reported in the medical literature in individuals with osteogenesis imperfecta but is reported in … (more) The BMP1 c.2134G>A; p.Gly712Ser variant (rs117159093), to our knowledge, is not reported in the medical literature in individuals with osteogenesis imperfecta but is reported in ClinVar (Variation ID: 498501). This variant is found in the non-Finnish European population with an allele frequency of 0.1382% (176/127,382 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.858). Due to limited information, the clinical significance of this variant is uncertain at this time. (less)
Uncertain significance (Jun 18, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005409422.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (1) PubMed: 37076969 Comment: BS1, PP3 Number of individuals with the variant: 1

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 712 of the BMP1 protein (p.Gly712Ser). This variant is present in population databases (rs117159093, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with BMP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 498501). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Reported in a patient with an atypical femur fracture, however a second BMP1 variant was not identified (Zhou et al., 2023); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37076969, PollitR2019[thesis])

Comment:

The BMP1 c.2134G>A; p.Gly712Ser variant (rs117159093), to our knowledge, is not reported in the medical literature in individuals with osteogenesis imperfecta but is reported in ClinVar (Variation ID: 498501). This variant is found in the non-Finnish European population with an allele frequency of 0.1382% (176/127,382 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.858). Due to limited information, the clinical significance of this variant is uncertain at this time.

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
Prevalence of Monogenic Bone Disorders in a Dutch Cohort of Atypical Femur Fracture Patients.	Zhou W	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research	2023	PMID: 37076969
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BMP1	-	-	-	-

Text-mined citations for rs117159093 ...

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 Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_006129.5(BMP1):c.2134G>A (p.Gly712Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs117159093 ...