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dc.contributor.authorCaswell, RC
dc.contributor.authorOwens, MM
dc.contributor.authorGunning, AC
dc.contributor.authorEllard, S
dc.contributor.authorWright, CF
dc.date.accessioned2019-10-29T10:26:42Z
dc.date.issued2019-08-27
dc.description.abstractDespite the rapid expansion in recent years of databases reporting either benign or pathogenic genetic variation, the interpretation of novel missense variants can remain challenging, particularly for clinical or genetic testing laboratories where functional analysis is often unfeasible. Previous studies have shown that thermodynamic analysis of protein structure in silico can discriminate between groups of benign and pathogenic missense variants. However, although structures exist for many human disease-associated proteins, such analysis remains largely unexploited in clinical laboratories. Here, we analysed the predicted effect of 338 known missense variants on the structure of menin, the MEN1 gene product. Results provided strong discrimination between pathogenic and benign variants, with a threshold of >4 kcal/mol for the predicted change in stability providing a strong indicator of pathogenicity. Subsequent analysis of 7 novel missense variants identified during clinical testing of MEN1 patients showed that all 7 were predicted to destabilise menin by >4 kcal/mol. We conclude that structural analysis provides a useful tool in understanding the impact of missense variants in MEN1, and that integration of proteomic with genomic data could potentially contribute to the classification of novel variants in this disease.en_GB
dc.description.sponsorshipWellcome Trusten_GB
dc.identifier.citationPublished online 27 September 2019en_GB
dc.identifier.doi10.1210/js.2019-00260
dc.identifier.grantnumber200990en_GB
dc.identifier.urihttp://hdl.handle.net/10871/39361
dc.language.isoenen_GB
dc.publisherEndocrine Societyen_GB
dc.rights© 2019 Endocrine Society. Open access. This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).en_GB
dc.subjectMultiple Endocrine Neoplasia type 1en_GB
dc.subjectprotein structureen_GB
dc.subjectmissense variant interpretationen_GB
dc.subjectgenomicsen_GB
dc.titleUsing structural analysis in silico to assess the impact of missense variants in MEN1en_GB
dc.typeArticleen_GB
dc.date.available2019-10-29T10:26:42Z
dc.descriptionThis is the author accepted manuscript. The final version is available from the Endocrine Society via the DOI in this recorden_GB
dc.descriptionData availability: All data generated or analysed during this study are included or cited in this published article, with the exception of DDG and RSA values calculated from individual PDB structures and subsequently used to calculate average values for each variant (38). This data is available from the corresponding author on reasonable requesten_GB
dc.identifier.eissn2472-1972
dc.identifier.journalJournal of the Endocrine Societyen_GB
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_GB
dcterms.dateAccepted2019-09-20
rioxxterms.versionAMen_GB
rioxxterms.licenseref.startdate2019-09-20
rioxxterms.typeJournal Article/Reviewen_GB
refterms.dateFCD2019-10-29T10:24:57Z
refterms.versionFCDAM
refterms.dateFOA2019-10-29T10:26:46Z
refterms.panelAen_GB


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© 2019 Endocrine Society. Open access. 
This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).
Except where otherwise noted, this item's licence is described as © 2019 Endocrine Society. Open access. This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).