VCV000258640.21 - ClinVar

NM_002335.4(LRP5):c.3989C>T (p.Ala1330Val)

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.

(11)

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_002335.4(LRP5):c.3989C>T (p.Ala1330Val)

Variation ID: 258640 Accession: VCV000258640.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.2 11: 68201295 (GRCh37) [ NCBI UCSC ] 11: 68433827 (GRCh38) [ 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	Oct 3, 2016	Sep 29, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002335.4:c.3989C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002326.2:p.Ala1330Val	missense
NM_001291902.2:c.2246C>T	NP_001278831.1:p.Ala749Val	missense
NC_000011.10:g.68433827C>T
NC_000011.9:g.68201295C>T
NG_015835.2:g.126188C>T
	O75197:p.Ala1330Val

... more HGVS ... less HGVS

Protein change

A1330V, A749V

Other names

Canonical SPDI

NC_000011.10:68433826:C:T

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.

0.11601 (T)

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

The Genome Aggregation Database (gnomAD) 0.10701

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.10923

1000 Genomes Project 30x 0.11305

1000 Genomes Project 0.11601

Trans-Omics for Precision Medicine (TOPMed) 0.12161

The Genome Aggregation Database (gnomAD), exomes 0.13410

Exome Aggregation Consortium (ExAC) 0.13917

Links

ClinGen: CA6150180 UniProtKB: O75197#VAR_021817 dbSNP: rs3736228 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.
LRP5		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2064	2081

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 (3)	criteria provided, multiple submitters, no conflicts	Jul 14, 2015	RCV000242123.11
not provided	Benign (5)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000712234.12
Osteoporosis with pseudoglioma	Benign (1)	criteria provided, single submitter	May 28, 2019	RCV000988589.1
Increased bone mineral density	Benign (1)	criteria provided, single submitter	Mar 31, 2021	RCV002278174.3
Osteogenesis imperfecta	Benign (1)	criteria provided, single submitter	Jul 18, 2022	RCV002278173.3

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: SCV000308845.1 First in ClinVar: Oct 03, 2016 Last updated: Oct 03, 2016
Benign (Jul 14, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331773.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LRP5 Sex: mixed
Benign (May 24, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000842678.1 First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018	Publications: PubMed (24) PubMed: 15767861‚ 15777745‚ 15824851‚ 17086708‚ 17137849‚ 17202888‚ 17223614‚ 17241106‚ 17306638‚ 17307038‚ 17505772‚ 17766366‚ 18058054‚ 18349089‚ 18493104‚ 18588671‚ 18932002‚ 19023643‚ 11793484‚ 12579474‚ 14727154‚ 15077203‚ 15201508‚ 15619672
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Osteoporosis with pseudoglioma Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001138366.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001862900.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 33302760, 25580429, 30283887, 16355283, 18026682, 16713434, 18455228, 18349089, 17955262, 19571442, 21432225, 18058054, 22511589, 21116122)
Benign (Mar 31, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Increased bone mineral density Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002564676.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Benign (Jul 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002564901.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Benign (Jan 31, 2024)	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: SCV001729688.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005319255.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001809510.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952402.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A1330V polymorphism of low-density lipoprotein receptor-related protein 5 gene and self-reported incident fractures in Japanese female patients with rheumatoid arthritis.	Furuya T	Modern rheumatology	2009	PMID: 19023643
Association between the A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene and bone mineral density: a meta-analysis.	Lee YH	Rheumatology international	2009	PMID: 18932002
Association between LRP5 polymorphism and bone mineral density: a Bayesian meta-analysis.	Tran BN	BMC medical genetics	2008	PMID: 18588671
Lack of association of LRP5 and LRP6 polymorphisms with type 2 diabetes mellitus in the Japanese population.	Zenibayashi M	Endocrine journal	2008	PMID: 18493104
Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis.	van Meurs JB	JAMA	2008	PMID: 18349089
Genetic risk for metabolic syndrome: examination of candidate gene polymorphisms related to lipid metabolism in Japanese people.	Yamada Y	Journal of medical genetics	2008	PMID: 17766366
Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with peak bone mass in non-sedentary men: results from the Odense androgen study.	Brixen K	Calcified tissue international	2007	PMID: 18058054
The effect of LRP5 polymorphisms on bone mineral density is apparent in childhood.	Koay MA	Calcified tissue international	2007	PMID: 17505772
LRP5 coding polymorphisms influence the variation of peak bone mass in a normal population of French-Canadian women.	Giroux S	Bone	2007	PMID: 17307038
Association of a single-nucleotide variation (A1330V) in the low-density lipoprotein receptor-related protein 5 gene (LRP5) with bone mineral density in adult Japanese women.	Ezura Y	Bone	2007	PMID: 17306638
Low-density lipoprotein receptor-related protein 5 (LRP5) gene polymorphisms are associated with bone mass in both Chinese and whites.	Xiong DH	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research	2007	PMID: 17241106
The A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene (LRP5) associates with low peak bone mass in young healthy men.	Saarinen A	Bone	2007	PMID: 17223614
Q89R polymorphism in the LDL receptor-related protein 5 gene is associated with spinal osteoarthritis in postmenopausal Japanese women.	Urano T	Spine	2007	PMID: 17202888
Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men.	Kiel DP	Bone	2007	PMID: 17137849
[Association of polymorphism of low density lipoprotein receptor-related protein 5 Q89R, A1330V with bone mineral density in premenopausal northern Chinese women].	Li Y	Wei sheng yan jiu = Journal of hygiene research	2006	PMID: 17086708
Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children.	Hartikka H	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research	2005	PMID: 15824851
LRP5 gene polymorphisms predict bone mass and incident fractures in elderly Australian women.	Bollerslev J	Bone	2005	PMID: 15777745
Pathogenic mutations and polymorphisms in the lipoprotein receptor-related protein 5 reveal a new biological pathway for the control of bone mass.	Ferrari SL	Current opinion in lipidology	2005	PMID: 15767861
Contribution of the LRP5 gene to normal variation in peak BMD in women.	Koller DL	Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research	2005	PMID: 15619672
Association between bone mineral density and LDL receptor-related protein 5 gene polymorphisms in young Korean men.	Koh JM	Journal of Korean medical science	2004	PMID: 15201508
Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites.	Ferrari SL	American journal of human genetics	2004	PMID: 15077203
LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density.	Mizuguchi T	Journal of human genetics	2004	PMID: 14727154
Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density.	Van Wesenbeeck L	American journal of human genetics	2003	PMID: 12579474
Seven novel sequence variants in the human low density lipoprotein receptor related protein 5 (LRP5) gene.	Okubo M	Human mutation	2002	PMID: 11793484
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LRP5	-	-	-	-
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Text-mined citations for rs3736228 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_002335.4(LRP5):c.3989C>T (p.Ala1330Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs3736228 ...