ClinVar Miner

Submissions for variant NM_001122681.2(SH3BP2):c.1253C>G (p.Pro418Arg)

dbSNP: rs121909146
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000486508 SCV000339310 pathogenic not provided 2016-01-26 criteria provided, single submitter clinical testing
GeneDx RCV000486508 SCV000565561 pathogenic not provided 2021-10-22 criteria provided, single submitter clinical testing 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)
Invitae RCV000007984 SCV001222625 pathogenic Fibrous dysplasia of jaw 2023-08-25 criteria provided, single submitter clinical testing 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).
Molecular Genetics, Royal Melbourne Hospital RCV000007984 SCV004812397 pathogenic Fibrous dysplasia of jaw 2022-07-01 criteria provided, single submitter clinical testing 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.
OMIM RCV000007984 SCV000028189 pathogenic Fibrous dysplasia of jaw 2001-06-01 no assertion criteria provided literature only

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