2026-05-22T17:24:06Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/112352024-09-27T08:29:19Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Pricolo, Maria Rosaria
author
Herrero-Galan, Elas
author
Mazzaccara, Cristina
author
Losi, Maria Angela
author
Alegre-Cebollada, Jorge
author
Frisso, Giulia
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Comunidad de Madrid (España)
funder
Centro Nacional de Investigaciones Cardiovasculares Carlos III (España)
funder
Instituto de Salud Carlos III
funder
Ministero dell Istruzione (Italia)
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Fundación ProCNIC
2020-10-28T09:11:14Z
2020-10-28T09:11:14Z
2020-10
J Cardiovasc Transl Res. 2020; 13(5):867-877
10.1007/s12265-020-09959-6
1937-5387
Journal of cardiovascular translational research
32034629
http://hdl.handle.net/20.500.12105/11235
In the era of next generation sequencing (NGS), genetic testing for inherited disorders identifies an ever-increasing number of variants whose pathogenicity remains unclear. These variants of uncertain significance (VUS) limit the reach of genetic testing in clinical practice. The VUS for hypertrophic cardiomyopathy (HCM), the most common familial heart disease, constitute over 60% of entries for missense variants shown in ClinVar database. We have studied a novel VUS (c.1809T>G-p.I603M) in the most frequently mutated gene in HCM, MYBPC3, which codes for cardiac myosin-binding protein C (cMyBPC). Our determinations of pathogenicity integrate bioinformatics evaluation and functional studies of RNA splicing and protein thermodynamic stability. In silico prediction and mRNA analysis indicated no alteration of RNA splicing induced by the variant. At the protein level, the p.I603M mutation maps to the C4 domain of cMyBPC. Although the mutation does not perturb much the overall structure of the C4 domain, the stability of C4 I603M is severely compromised as detected by circular dichroism and differential scanning calorimetry experiments. Taking into account the highly destabilizing effect of the mutation in the structure of C4, we propose reclassification of variant p.I603M as likely pathogenic. Looking into the future, the workflow described here can be used to refine the assignment of pathogenicity of variants of uncertain significance in MYBPC3.
eng
Protein Thermodynamic Destabilization in the Assessment of Pathogenicity of a Variant of Uncertain Significance in Cardiac Myosin Binding Protein C.
journal article
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ProteinThermodynamicDestabilizationAssessment_20202_Figure.pdf
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ProteinThermodynamicDestabilizationAssessment_20202_Figure.pdf.txt
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