ClinVar Genomic variation as it relates to human health
NM_001122681.2(SH3BP2):c.1253C>G (p.Pro418Arg)
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
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NM_001122681.2(SH3BP2):c.1253C>G (p.Pro418Arg)
Variation ID: 7548 Accession: VCV000007548.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.3 4: 2831582 (GRCh38) [ NCBI UCSC ] 4: 2833309 (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 Apr 4, 2013 Apr 15, 2024 Aug 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001122681.2:c.1253C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001116153.1:p.Pro418Arg missense NM_001145855.2:c.1337C>G NP_001139327.1:p.Pro446Arg missense NM_001145856.2:c.1424C>G NP_001139328.1:p.Pro475Arg missense NM_003023.4:c.1253C>G NP_003014.3:p.Pro418Arg missense NC_000004.12:g.2831582C>G NC_000004.11:g.2833309C>G NG_011609.1:g.43560C>G LRG_1334:g.43560C>G LRG_1334t1:c.1253C>G LRG_1334p1:p.Pro418Arg LRG_1334t2:c.1337C>G LRG_1334p2:p.Pro446Arg P78314:p.Pro418Arg - Protein change
- P418R, P446R, P475R
- Other names
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- Canonical SPDI
- NC_000004.12:2831581:C:G
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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SH3BP2 | - | - |
GRCh38 GRCh37 |
731 | 865 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 25, 2023 | RCV000007984.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 22, 2021 | RCV000486508.9 |
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
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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
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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
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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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Pathogenic
(Aug 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fibrous dysplasia of jaw
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001222625.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro418 amino acid residue in SH3BP2. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro418 amino acid residue in SH3BP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17321449, 23298620, 28644570). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SH3BP2 function (PMID: 21794028, 22153076, 22153077, 24916406, 25144740). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SH3BP2 protein function. ClinVar contains an entry for this variant (Variation ID: 7548). This missense change has been observed in individual(s) with cherubism (PMID: 11381256, 14577811, 18596838, 30236129). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 418 of the SH3BP2 protein (p.Pro418Arg). (less)
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Pathogenic
(Jul 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fibrous dysplasia of jaw
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812397.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in SH3BP2 is predicted to replace proline with arginine at codon 418, p.(Pro418Arg). The proline residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in SH3BP2 is predicted to replace proline with arginine at codon 418, p.(Pro418Arg). The proline residue is highly conserved (100 vertebrates, UCSC), and is located within the RSPPDG peptide sequence lying between the PH and SH2 domains, amino acids 415-420, which is defined as a mutational hotspot (PMID: 22640988). There is a large physicochemical difference between proline and arginine. This variant is absent from gnomAD v2.1 and v3.1. This is the most commonly reported variant in families with a clinical diagnosis of Cherubism (PMID: 11381256, 22640988, 30236129). Functional assays demonstrate that the variant causes a gain-of-function by increasing the interaction with specific signalling molecules and a homozygous Sh3bp2 Pro416Arg knock-in mouse model recapitulates the human cherubism phenotype (PMID: 17218256, 20117257, 21794028). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PS4, PM1, PM2_Supporting, PP3. (less)
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Pathogenic
(Jan 26, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000339310.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Sex: mixed
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Pathogenic
(Oct 22, 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: SCV000565561.6
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate P418R causes gain of function by increasing interaction of B cells with specific signaling molecules (Lietman et al., 2006; Levaot et … (more)
Published functional studies demonstrate P418R causes gain of function by increasing interaction of B cells with specific signaling molecules (Lietman et al., 2006; Levaot et al., 2011; Ogi et al., 2011; Mukai et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 22153077, 24916406, 21794028, 25144740, 16786512, 20691350, 11381256, 18596838, 14577811, 29669173, 30236129, 28904407, 22153076, 27498064) (less)
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Pathogenic
(Jun 01, 2001)
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no assertion criteria provided
Method: literature only
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CHERUBISM
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028189.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Ueki et al. (2001) found a pro418-to-arg (P418R) mutation of the SH3BP2 gene in patients with cherubism (118400).
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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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Molecular and cellular characterizations of human cherubism: disease aggressiveness depends on osteoclast differentiation. | Kadlub N | Orphanet journal of rare diseases | 2018 | PMID: 30236129 |
Clinical and genetic analysis of patients with cherubism. | Machado RA | Oral diseases | 2017 | PMID: 28644570 |
SH3BP2 gain-of-function mutation exacerbates inflammation and bone loss in a murine collagen-induced arthritis model. | Mukai T | PloS one | 2014 | PMID: 25144740 |
SH3BP2 cherubism mutation potentiates TNF-α-induced osteoclastogenesis via NFATc1 and TNF-α-mediated inflammatory bone loss. | Mukai T | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2014 | PMID: 24916406 |
Characterization of a Norwegian cherubism cohort; molecular genetic findings, oral manifestations and quality of life. | Prescott T | European journal of medical genetics | 2013 | PMID: 23298620 |
The role of SH3BP2 in the pathophysiology of cherubism. | Reichenberger EJ | Orphanet journal of rare diseases | 2012 | PMID: 22640988 |
Structural basis and sequence rules for substrate recognition by Tankyrase explain the basis for cherubism disease. | Guettler S | Cell | 2011 | PMID: 22153077 |
Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism. | Levaot N | Cell | 2011 | PMID: 22153076 |
Pro416Arg cherubism mutation in Sh3bp2 knock-in mice affects osteoblasts and alters bone mineral and matrix properties. | Wang CJ | Bone | 2010 | PMID: 20117257 |
A new mutation in the SH3BP2 gene showing reduced penetrance in a family affected with cherubism. | de Lange J | Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics | 2007 | PMID: 17321449 |
Increased myeloid cell responses to M-CSF and RANKL cause bone loss and inflammation in SH3BP2 "cherubism" mice. | Ueki Y | Cell | 2007 | PMID: 17218256 |
Identification of a novel mutation of SH3BP2 in cherubism and demonstration that SH3BP2 mutations lead to increased NFAT activation. | Lietman SA | Human mutation | 2006 | PMID: 16786512 |
Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. | Ueki Y | Nature genetics | 2001 | PMID: 11381256 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SH3BP2 | - | - | - | - |
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Text-mined citations for rs121909146 ...
HelpRecord last updated Apr 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.