scholarly journals S-CAP extends clinical-grade pathogenicity prediction to genetic variants that affect RNA splicing

2018 ◽  
Author(s):  
Karthik A. Jagadeesh ◽  
Joseph M. Paggi ◽  
James S. Ye ◽  
Peter D. Stenson ◽  
David N. Cooper ◽  
...  
Keyword(s):  
Genetic Variants ◽  
In Silico ◽  
Rna Splicing ◽  
Clinical Grade ◽  
Inherited Disease ◽  
Variants Of Uncertain Significance ◽  
Pathogenicity Prediction ◽  
Uncertain Significance ◽  
Human Inherited Disease

AbstractThere are over 15,000 known variants that cause human inherited disease by disrupting RNA splicing. While several in silico methods such as CADD, EIGEN and LINSIGHT are commonly used to predict the pathogenicity of noncoding variants, we introduce S-CAP, a tool developed specially for splicing which is better able to effectively distinguish pathogenic splicing-relevant variants from benign variants. S-CAP is a novel splicing pathogenicity predictor that reduces the number of splicing-relevant variants of uncertain significance in patient exomes by 41%, a nearly 3-fold improvement over existing noncoding pathogenicity measures while correctly classifying known pathogenic splicing-relevant variants with a clinical-grade 95% sensitivity.

In Silico Identification of Protein S-Palmitoylation Sites and Their Involvement in Human Inherited Disease

2015 ◽  
Vol 55 (9) ◽  
pp. 2015-2025 ◽  
Author(s):  
Shuyan Li ◽  
Jiazhong Li ◽  
Lulu Ning ◽  
Shaopeng Wang ◽  
Yuzhen Niu ◽  
...  
Keyword(s):  
In Silico ◽  
Protein S ◽  
Inherited Disease ◽  
In Silico Identification ◽  
Human Inherited Disease

scholarly journals Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance

2016 ◽  
Vol 1 (1) ◽  
Author(s):  
Nicholas T Woods ◽  
Rebekah Baskin ◽  
Volha Golubeva ◽  
Ankita Jhuraney ◽  
Giuliana De-Gregoriis ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Variants Of Uncertain Significance ◽  
Functional Assays ◽  
Uncertain Significance ◽  
Clinical Annotation

scholarly journals Thermodynamic destabilization informs pathogenicity assessment of a variant of uncertain significance in cardiac myosin binding protein C

2019 ◽  
Author(s):  
Maria Rosaria Pricolo ◽  
Elías Herrero-Galán ◽  
Cristina Mazzaccara ◽  
Maria Angela Losi ◽  
Jorge Alegre-Cebollada ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Rna Splicing ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Variants Of Uncertain Significance ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Uncertain Significance ◽  
Myosin Binding

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 in MYBPC3.

scholarly journals BRCA1 and BRCA2 mutations in breast and ovarian cancer families from south west Colombia

2020 ◽  
pp. 163-175
Author(s):  
Laura Cifuentes-C ◽  
Ana Lucia Rivera-Herrera ◽  
Guillermo Barreto
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
In Silico ◽  
Novel Mutation ◽  
In Silico Analysis ◽  
Moderate Increase ◽  
Brca1 And Brca2 ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance ◽  
Colombian Pacific

Introduction: Breast cancer is the most common neoplasia of women from all over the world especially women from Colombia. 5%­10% of all cases are caused by hereditary factors, 25% of those cases have mutations in the BRCA1/BRCA2 genes. Objective: The purpose of this study was to identify the mutations associated with the risk of familial breast and/or ovarian cancer in a population of Colombian pacific. Methods: 58 high-risk breast and/or ovarian cancer families and 20 controls were screened for germline mutations in BRCA1 and BRCA2, by Single Strand Conformation Polymorphism (SSCP) and sequencing. Results: Four families (6.9%) were found to carry BRCA1 mutations and eight families (13.8%) had mutations in BRCA2. In BRCA1, we found three Variants of Uncertain Significance (VUS), of which we concluded, using in silico tools, that c.81­12C>G and c.3119G>A (p.Ser1040Asn) are probably deleterious, and c.3083G>A (p.Arg1028His) is probably neutral. In BRCA2, we found three variants of uncertain significance: two were previously described and one novel mutation. Using in silico analysis, we concluded that c.865A>G (p.Asn289Asp) and c.6427T>C (p.Ser2143Pro) are probably deleterious and c.125A>G (p.Tyr42Cys) is probably neutral. Only one of them has previously been reported in Colombia. We also identified 13 polymorphisms (4 in BRCA1 and 9 in BRCA2), two of them are associated with a moderate increase in breast cancer risk (BRCA2 c.1114A>C and c.8755­66T>C). Conclusion: According to our results, the Colombian pacific population presents diverse mutational spectrum for BRCA genes that differs from the findings in other regions in the country.

Variants of Uncertain Significance inBRCA1andBRCA2assessment of in silico analysis and a proposal for communication in genetic counselling

2012 ◽  
Vol 50 (2) ◽  
pp. 74-79 ◽  
Author(s):  
Setareh Moghadasi ◽  
Nandy Hofland ◽  
Joyce N Wouts ◽  
Frans B L Hogervorst ◽  
Juul T Wijnen ◽  
...  
Keyword(s):  
Genetic Counselling ◽  
In Silico ◽  
In Silico Analysis ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance ◽  
Silico Analysis

scholarly journals Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants

2020 ◽  
Vol 9 (3) ◽  
Author(s):  
Tess D. Pottinger ◽  
Megan J. Puckelwartz ◽  
Lorenzo L. Pesce ◽  
Avery Robinson ◽  
Samuel Kearns ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Genetic Variants ◽  
African Ancestry ◽  
Left Ventricular ◽  
Whole Genome Sequence ◽  
European Ancestry ◽  
Internal Diameter ◽  
Variants Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Uncertain Significance

Background Genome sequencing coupled with electronic heath record data can uncover medically important genetic variation. Interpretation of rare genetic variation and its role in mediating cardiovascular phenotypes is confounded by variants of uncertain significance. Methods and Results We analyzed the whole genome sequence of 900 racially and ethnically diverse biobank participants selected from a single US center. Participants were equally divided among European, African, Hispanic, and mixed races/ethnicities. We evaluated the American College of Medical Genetics and Genomics medically actionable list of 59 genes, focusing on the cardiac genes. Variation was interpreted using the most recent reports in ClinVar, a database of medically relevant human variation. We identified 19 individuals with pathogenic or likely pathogenic variants in cardiac actionable genes (2%) and found evidence of related clinical correlates in the electronic health record. Participants of African ancestry, compared with those of European ancestry, had more variants of uncertain significance in the medically actionable genes including the 30 cardiac actionable genes, even when normalized to total variant count per person. Longitudinal measures of left ventricle size from ≈400 biobank participants (1723 patient‐years) were correlated with genetic findings. The presence of ≥1 uncertain variant in the actionable cardiac genes and a cardiomyopathy diagnosis correlated with increased left ventricular internal diameter in diastole and in systole. In particular, MYBPC 3 was identified as a gene with excess variants of uncertain significance. Conclusions These data indicate that a subset of uncertain genetic variants may confer risk and should not be considered benign.

GENETIC VARIANTS OF UNCERTAIN SIGNIFICANCE (VUS) IN FAMILIAL HYPERCHOLESTEROLAEMIA (FH) IN WALES: YEAR 2 UPDATE

2016 ◽  
Vol 245 ◽  
pp. e246
Author(s):  
K. Haralambos ◽  
S.D. Whatley ◽  
R. Edwards ◽  
R. Gingell ◽  
D. Townsend ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Familial Hypercholesterolaemia ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance
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