Dataset Information

'A variant of uncertain significance' and the proliferation of human disease gene databases.

ABSTRACT: The rapid accumulation of mutation data has led to the creation of nearly 300 locus-specific mutation databases. These sites may contain a few dozen to almost 20,000 mutations for a given gene. Many of the mutations are uncharacterised and have no known effects on the gene product, the 'variant of uncertain significance'. Here, the statistics of mutation distribution are examined for six different gene databases: BRCA1 and BRCA2, haemoglobin-beta (HBB), HPRT1, CFTR and TP53. The percentage of all possible point mutations for a protein (the mutation space) is calculated for each gene and the question 'How much mutation data is enough?' is raised.

SUBMITTER: Nelson DR

PROVIDER: S-EPMC3525115 | biostudies-other | 2005 Mar

REPOSITORIES: biostudies-other

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'A variant of uncertain significance' and the proliferation of human disease gene databases.

Nelson David R DR

Human genomics 20050301 1

The rapid accumulation of mutation data has led to the creation of nearly 300 locus-specific mutation databases. These sites may contain a few dozen to almost 20,000 mutations for a given gene. Many of the mutations are uncharacterised and have no known effects on the gene product, the 'variant of uncertain significance'. Here, the statistics of mutation distribution are examined for six different gene databases: BRCA1 and BRCA2, haemoglobin-beta (HBB), HPRT1, CFTR and TP53. The percentage of al ...[more]

PMID: 15814069

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Project description:BACKGROUND:The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants of uncertain significance (VUS) in both patients and asymptomatic "healthy" individuals. A VUS is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded, and thus cannot be definitively annotated. VUS, therefore, pose critical clinical interpretation and risk-assessment challenges, and new methods are urgently needed to better characterize their pathogenicity. METHODS:To address this challenge and showcase the uncertainty surrounding genomic variant interpretation, we recruited a "healthy" asymptomatic individual, lacking cardiac-disease clinical history, carrying a hypertrophic cardiomyopathy (HCM)-associated genetic variant (NM_000258.2:c.170C>A, NP_000249.1:p.Ala57Asp) in the sarcomeric gene MYL3, reported by the ClinVar database to be "likely pathogenic." Human-induced pluripotent stem cells (iPSCs) were derived from the heterozygous VUS MYL3(170C>A) carrier, and their genome was edited using CRISPR/Cas9 to generate 4 isogenic iPSC lines: (1) corrected "healthy" control; (2) homozygous VUS MYL3(170C>A); (3) heterozygous frameshift mutation MYL3(170C>A/fs); and (4) known heterozygous MYL3 pathogenic mutation (NM_000258.2:c.170C>G), at the same nucleotide position as VUS MYL3(170C>A), lines. Extensive assays including measurements of gene expression, sarcomere structure, cell size, contractility, action potentials, and calcium handling were performed on the isogenic iPSC-derived cardiomyocytes (iPSC-CMs). RESULTS:The heterozygous VUS MYL3(170C>A)-iPSC-CMs did not show an HCM phenotype at the gene expression, morphology, or functional levels. Furthermore, genome-edited homozygous VUS MYL3(170C>A)- and frameshift mutation MYL3(170C>A/fs)-iPSC-CMs lines were also asymptomatic, supporting a benign assessment for this particular MYL3 variant. Further assessment of the pathogenic nature of a genome-edited isogenic line carrying a known pathogenic MYL3 mutation, MYL3(170C>G), and a carrier-specific iPSC-CMs line, carrying a MYBPC3(961G>A) HCM variant, demonstrated the ability of this combined platform to provide both pathogenic and benign assessments. CONCLUSIONS:Our study illustrates the ability of clustered regularly interspaced short palindromic repeats/Cas9 genome-editing of carrier-specific iPSCs to elucidate both benign and pathogenic HCM functional phenotypes in a carrier-specific manner in a dish. As such, this platform represents a promising VUS risk-assessment tool that can be used for assessing HCM-associated VUS specifically, and VUS in general, and thus significantly contribute to the arsenal of precision medicine tools available in this emerging field.

Dataset Information

'A variant of uncertain significance' and the proliferation of human disease gene databases.

Publications

'A variant of uncertain significance' and the proliferation of human disease gene databases.

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