Protein Thermodynamic Destabilization in the Assessment of Pathogenicity of a Variant of Uncertain Significance in Cardiac Myosin Binding Protein C

AbstractIn 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 inMYBPC3.
Source: Journal of Cardiovascular Translational Research - Category: Cardiology Source Type: research

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Discussion Tachycardia is a rapid heart rate that is above normal for age and level of exertion. Tachycardia is common, particularly sinus tachycardia due to normally encountered circumstances such as pain, fever or exercise. It is usually a normal physiologic process but sustained tachycardia often indicates a potentially abnormal underlying cause. Sinus tachycardia has a rapid heart rate with normal P waves and P-R intervals and variations from moment to moment and respiration. Generally it is not over 200 beats/minute. Vagal stimulation can slow the heart rate; this is a gradual slowing, not an abrupt slowing seen in ...
Source: - Category: Pediatrics Authors: Tags: Uncategorized Source Type: news
This study aimed to evaluate the potential of estrogen therapy and regular exercise on attenuating cardiac inflammation in the context of doxorubicin-induced cardiomyopathy. Ovariectomized rats were randomly allocated into estrogen supplementation, exercise training, and mast cell stabilizer treatment groups. Eight weeks after ovariectomy, rats received six cumulative doses of doxorubicin for two weeks. Echocardiography demonstrated a progressive decrease in ejection fraction in doxorubicin-treated rats without hypertrophic effect. This systolic defect was completely prevented by either estrogen supplementation or mast cel...
Source: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology - Category: Physiology Authors: Tags: Am J Physiol Regul Integr Comp Physiol Source Type: research
Conclusions: Our data suggest that integrin β1D deficiency represents a novel mechanism underlying the increased risk of ventricular arrhythmias in patients with ARVC. PMID: 32122157 [PubMed - as supplied by publisher]
Source: Circulation - Category: Cardiology Authors: Tags: Circulation Source Type: research
Authors: Elwazir MY, Bois JP, Abouezzeddine OF, Chareonthaitawee P Abstract Infiltrative heart disease is an encompassing term referring to different pathological entities that involve infiltration of the myocardium by either abnormal substances or inflammatory cells. These infiltrates can impair cellular function, induce necrosis and fibrosis, or otherwise disrupt myocardial architecture resulting in a wide spectrum of structural and functional impairment. Depending on the specific disorder and stage of disease, patients may present with minimal cardiac abnormalities, or may have findings of advanced restrictive a...
Source: Quarterly Journal of Nuclear Medicine and Molecular Imaging - Category: Nuclear Medicine Tags: Q J Nucl Med Mol Imaging Source Type: research
This study investigated ICD-lead intracardiac parameters over a long duration in patients with ARVC and HCM and compared these parameters with those of a control group. We included 50 patients (mean age, 55.2 ± 17.2 years; 26% female) with ICD leads in the right ventricular apex, and compared 7 ARVC and 14 HCM patients with 29 control patients without structural heart disease. ICD-lead parameters, including R-wave amplitude, pacing threshold, and impedance during follow-up, were compared. The difference in these parameters between the time of implantation and year 5 were also compared. There were no significant diff...
Source: International Heart Journal - Category: Cardiology Tags: Int Heart J Source Type: research
We examined frequency, clinical characteristics and AF‐related management and outcomes amongst this patient population.MethodsWe retrospectively studied consecutive probands with inherited cardiomyopathy (n=962) and inherited arrhythmia syndromes (n=195) evaluated between 2002 ‐2018.ResultsAF was observed in 5 ‐31% of patients, with the highest frequency in HCM. Age of AF onset was 45.8 ± 21.9 years in the inherited arrhythmia syndromes compared to 53.3 ± 15.3 years in the inherited cardiomyopathies, with 4 CPVT patients developing AF at median age of 20 years. Overall, 11% of patients with AF had a t r...
Source: Journal of Cardiovascular Electrophysiology - Category: Cardiology Authors: Tags: ORIGINAL ARTICLE Source Type: research
This article discusses diagnostic criteria, treatments, and critical care nursing interventions, including patient teaching, for adults with HCM.
Source: Nursing Critical Care - Category: Nursing Tags: Feature Source Type: research
CONCLUSIONS: The SS was useful in detecting patients with HCM with mild or no symptoms at the early stage. However, our study indicated that early detection of HCM is not associated with improvement in the prognosis of the patients. Further studies are needed. PMID: 31836272 [PubMed - as supplied by publisher]
Source: Journal of Cardiology - Category: Cardiology Authors: Tags: J Cardiol Source Type: research
In this study, p
Source: Arquivos Brasileiros de Cardiologia - Category: Cardiology Source Type: research
In this study, p
Source: Arquivos Brasileiros de Cardiologia - Category: Cardiology Source Type: research
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