ClinVar Genomic variation as it relates to human health
NM_002335.4(LRP5):c.724G>A (p.Ala242Thr)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002335.4(LRP5):c.724G>A (p.Ala242Thr)
Variation ID: 6282 Accession: VCV000006282.7
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.2 11: 68363784 (GRCh38) [ NCBI UCSC ] 11: 68131252 (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 Dec 6, 2016 Feb 14, 2024 Apr 12, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_002335.4:c.724G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002326.2:p.Ala242Thr missense NM_001291902.2:c.-1042G>A 5 prime UTR NC_000011.10:g.68363784G>A NC_000011.9:g.68131252G>A NG_015835.2:g.56145G>A O75197:p.Ala242Thr - Protein change
- A242T
- Other names
- -
- Canonical SPDI
- NC_000011.10:68363783:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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 | ||
---|---|---|---|---|---|---|
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 | Some evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2042 | 2059 |
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. |
---|---|---|---|---|
Likely pathogenic (2) |
criteria provided, single submitter
|
Nov 9, 2020 | RCV000006660.6 | |
Pathogenic (1) |
no assertion criteria provided
|
Mar 1, 2003 | RCV000006661.5 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 12, 2023 | RCV000383760.5 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Nov 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Worth disease
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934303.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
|
Pathogenic
(Oct 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329406.6
First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019 |
Comment:
The A242T variant in the LRP5 gene has been report previous in numerous patients diagnosed with high bone mass, osteopetrosis, osteosclerosis, endosteal hyperostosis, and Van … (more)
The A242T variant in the LRP5 gene has been report previous in numerous patients diagnosed with high bone mass, osteopetrosis, osteosclerosis, endosteal hyperostosis, and Van Buchem disease (Wang et al., 2013; Gregson et al., 2016; Van et al., 2003). In virtro functional studies demonstrated that protein harboring the A242T variant undergoes post-translational modification at a significantly lower level than wild-type and has significantly reduced interactions DKK1 protein in comparison to wild-type (Ai et al., 2005). The A242T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A242T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, this variant is pathogenic. (less)
|
|
Likely pathogenic
(Apr 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003440555.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individual(s) with clinical features of autosomal dominant high bone mass syndromes (PMID: 12579474, 23318847, 26348019). It has also … (more)
This missense change has been observed in individual(s) with clinical features of autosomal dominant high bone mass syndromes (PMID: 12579474, 23318847, 26348019). It has also been observed to segregate with disease in related individuals. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects LRP5 function (PMID: 18521528). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LRP5 protein function. ClinVar contains an entry for this variant (Variation ID: 6282). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 242 of the LRP5 protein (p.Ala242Thr). (less)
|
|
Pathogenic
(Mar 01, 2003)
|
no assertion criteria provided
Method: literature only
|
ENDOSTEAL HYPEROSTOSIS, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026843.4
First in ClinVar: Apr 04, 2013 Last updated: May 14, 2021 |
Comment on evidence:
Van Wesenbeeck et al. (2003) described a 724G-A transition in exon 4 of the LRP5 gene, resulting in an ala242-to-thr (A242T) mutation, in 2 previously … (more)
Van Wesenbeeck et al. (2003) described a 724G-A transition in exon 4 of the LRP5 gene, resulting in an ala242-to-thr (A242T) mutation, in 2 previously described families (kindreds A and B) from Portland, Oregon (Beals, 1976; Beals et al., 2001) in which members were affected with autosomal dominant endosteal hyperostosis (144750). The condition is characterized by cortical thickening of the long bones, with no alteration in external shape, and a remarkable resistance of the bone to fracture. The skeleton was normal in childhood; the affected patients had a normal height, proportion, intelligence, and longevity. Facial metamorphoses occurred in adolescence, as the forehead flattened, the mandible became elongated, and the gonial angle decreased. Torus palatinus developed in the hard palate, which could lead to malocclusion or loss of teeth. The clinical and radiographic features closely resembled those of the kindred described by Boyden et al. (2002), in whom a gly171-to-val mutation (G171V; 603506.0013) was identified. The A242T mutation was also present in a previously described Sardinian family (kindred D; Scopelliti et al., 1999) in which at least 5 members had osteosclerosis of the skull and enlarged mandible. The mutation was also present in a French family in which an affected proband and his brother had autosomal dominant osteopetrosis type I (OPTA1; 607634), osteomyelitis of the jaw, and hearing problems because of small auditory canals. X-rays showed diffuse osteosclerosis of the trabecular and cortical bone and osteosclerosis of the skull with enlargement of the cranial vault. (less)
|
|
Pathogenic
(Mar 01, 2003)
|
no assertion criteria provided
Method: literature only
|
OSTEOPETROSIS, AUTOSOMAL DOMINANT 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026844.4
First in ClinVar: Apr 04, 2013 Last updated: May 14, 2021 |
Comment on evidence:
Van Wesenbeeck et al. (2003) described a 724G-A transition in exon 4 of the LRP5 gene, resulting in an ala242-to-thr (A242T) mutation, in 2 previously … (more)
Van Wesenbeeck et al. (2003) described a 724G-A transition in exon 4 of the LRP5 gene, resulting in an ala242-to-thr (A242T) mutation, in 2 previously described families (kindreds A and B) from Portland, Oregon (Beals, 1976; Beals et al., 2001) in which members were affected with autosomal dominant endosteal hyperostosis (144750). The condition is characterized by cortical thickening of the long bones, with no alteration in external shape, and a remarkable resistance of the bone to fracture. The skeleton was normal in childhood; the affected patients had a normal height, proportion, intelligence, and longevity. Facial metamorphoses occurred in adolescence, as the forehead flattened, the mandible became elongated, and the gonial angle decreased. Torus palatinus developed in the hard palate, which could lead to malocclusion or loss of teeth. The clinical and radiographic features closely resembled those of the kindred described by Boyden et al. (2002), in whom a gly171-to-val mutation (G171V; 603506.0013) was identified. The A242T mutation was also present in a previously described Sardinian family (kindred D; Scopelliti et al., 1999) in which at least 5 members had osteosclerosis of the skull and enlarged mandible. The mutation was also present in a French family in which an affected proband and his brother had autosomal dominant osteopetrosis type I (OPTA1; 607634), osteomyelitis of the jaw, and hearing problems because of small auditory canals. X-rays showed diffuse osteosclerosis of the trabecular and cortical bone and osteosclerosis of the skull with enlargement of the cranial vault. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001977780.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978686.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
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 |
---|---|---|---|---|
Mutations in Known Monogenic High Bone Mass Loci Only Explain a Small Proportion of High Bone Mass Cases. | Gregson CL | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2016 | PMID: 26348019 |
The binding between sclerostin and LRP5 is altered by DKK1 and by high-bone mass LRP5 mutations. | Balemans W | Calcified tissue international | 2008 | PMID: 18521528 |
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 |
High bone density due to a mutation in LDL-receptor-related protein 5. | Boyden LM | The New England journal of medicine | 2002 | PMID: 12015390 |
Dominant endosteal hyperostosis. Skeletal characteristics and review of the literature. | Beals RK | The Journal of bone and joint surgery. American volume | 2001 | PMID: 11701785 |
[Van Buchem disease. Maxillofacial changes, diagnostic classification and general principles of treatment]. | Scopelliti D | Minerva stomatologica | 1999 | PMID: 10434540 |
Endosteal hyperostosis. | Beals RK | The Journal of bone and joint surgery. American volume | 1976 | PMID: 1002767 |
Text-mined citations for rs121908670 ...
HelpRecord last updated Feb 20, 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.