ClinVar Genomic variation as it relates to human health
NM_002335.4(LRP5):c.3107G>A (p.Arg1036Gln)
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.
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(6); Benign(1); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002335.4(LRP5):c.3107G>A (p.Arg1036Gln)
Variation ID: 183255 Accession: VCV000183255.55
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.2 11: 68423568 (GRCh38) [ NCBI UCSC ] 11: 68191036 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 7, 2015 Apr 15, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002335.4:c.3107G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002326.2:p.Arg1036Gln missense NM_001291902.2:c.1364G>A NP_001278831.1:p.Arg455Gln missense NC_000011.10:g.68423568G>A NC_000011.9:g.68191036G>A NG_015835.2:g.115929G>A O75197:p.Arg1036Gln - Protein change
- R1036Q, R455Q
- Other names
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- Canonical SPDI
- NC_000011.10:68423567:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00060 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00078
The Genome Aggregation Database (gnomAD) 0.00207
The Genome Aggregation Database (gnomAD), exomes 0.00249
Trans-Omics for Precision Medicine (TOPMed) 0.00323
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00408
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 | ||
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HI score
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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. |
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LRP5 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2035 | 2052 |
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. |
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not provided (1) |
no classification provided
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- | RCV000162089.1 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 23, 2022 | RCV000174732.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000765011.2 | |
Conflicting interpretations of pathogenicity (9) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV000767146.22 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 6, 2020 | RCV001260288.1 | |
Uncertain significance (1) |
no assertion criteria provided
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Sep 1, 2021 | RCV001844811.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 24, 2022 | RCV002277317.3 |
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. |
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Likely benign
(Nov 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000226093.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 6
Sex: mixed
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Exudative vitreoretinopathy 1
Worth disease Osteoporosis Osteoporosis with pseudoglioma Exudative vitreoretinopathy 4 Bone mineral density quantitative trait locus 1 Autosomal dominant osteopetrosis 1 Worth disease Polycystic liver disease 4 with or without kidney cysts
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000896195.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Apr 06, 2020)
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criteria provided, single submitter
Method: research
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Autosomal dominant osteopetrosis 1
Affected status: yes
Allele origin:
paternal
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Genetics Department, Polish Mother's Memorial Hospital Research Institute
Accession: SCV001244841.1
First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020 |
Number of individuals with the variant: 2
Sex: male
Ethnicity/Population group: Polish
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Likely benign
(Feb 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000589340.3
First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25920554, 22487062, … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25920554, 22487062, 27884173, 16390319, 15824851, 19673927, 28378289, 25390515, 31039433, 30652979, 33118644) (less)
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Uncertain significance
(Mar 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984237.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Likely benign
(Mar 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500604.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Uncertain significance
(Jun 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Osteogenesis imperfecta
Affected status: unknown
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002564888.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
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Uncertain significance
(Sep 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003812755.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004562978.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The LRP5 c.3107G>A; p.Arg1036Gln variant (rs61889560) is reported in the literature in individuals affected with osteoporosis (Caetano da Silva 2021, Hartikka 2005, Sturznickel 2021) or … (more)
The LRP5 c.3107G>A; p.Arg1036Gln variant (rs61889560) is reported in the literature in individuals affected with osteoporosis (Caetano da Silva 2021, Hartikka 2005, Sturznickel 2021) or polycystic kidney disease (Cnossen 2016), but did not segregate with disease in some families. This variant is also reported in ClinVar (Variation ID: 183255), and is found in the general population with an overall allele frequency of 0.24% (692/282864 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.683). In vitro functional analyses demonstrate reduced Wnt signaling, but no effect on expression of downstream genes (Cnossen 2016, Korvala 2012). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Caetano da Silva C et al. More severe phenotype of early-onset osteoporosis associated with recessive form of LRP5 and combination with DKK1 or WNT3A. Mol Genet Genomic Med. 2021 Jun;9(6):e1681. PMID: 33939331. Cnossen WR et al. LRP5 variants may contribute to ADPKD. Eur J Hum Genet. 2016 Feb;24(2):237-42. PMID: 25920554. Hartikka H et al. Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children. J Bone Miner Res. 2005 May;20(5):783-9. PMID: 15824851. Korvala J et al. Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity. BMC Med Genet. 2012 Apr 10;13:26. PMID: 22487062. Sturznickel J et al. Clinical Phenotype and Relevance of LRP5 and LRP6 Variants in Patients With Early-Onset Osteoporosis (EOOP). J Bone Miner Res. 2021 Feb;36(2):271-282. PMID: 33118644. (less)
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Likely benign
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033146.5
First in ClinVar: Sep 16, 2023 Last updated: Apr 15, 2024 |
Comment:
LRP5: BP4, BS2
Number of individuals with the variant: 3
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Benign
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001107121.5
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
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Uncertain significance
(Sep 01, 2021)
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no assertion criteria provided
Method: research
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Autosomal dominant polycystic kidney disease
Affected status: yes
Allele origin:
germline
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Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center
Accession: SCV001877025.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
Sex: female
Geographic origin: Netherlands
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001924263.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966621.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001797658.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809575.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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Polycystic kidney disease, adult type
Affected status: not provided
Allele origin:
germline
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Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center
Accession: SCV000212088.1
First in ClinVar: Mar 07, 2015 Last updated: Mar 07, 2015 |
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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
HelpTitle | Author | Journal | Year | Link |
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http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LRP5 | - | - | - | - |
Text-mined citations for rs61889560 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.