An openly available online tool for implementing the ACMG/AMP standards and guidelines for the interpretation of sequence variants

Kleinberger, Jeffrey W.; Maloney, Kristin A.; Pollin, Toni I.; Jeng, Linda Jo Bone

doi:10.1038/gim.2016.13

Cited by 105 publications

(91 citation statements)

References 2 publications

(2 reference statements)

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“…One de novo missense mutation in the EPHB2 gene was identified in proband H42, and the mutation was predicted to be damaging by 10 bioinformatics tools. The EPHB2 gene is involved in retinal axon projections via interactions with ephrin-B proteins (52). In addition, it was reported that the growth cone collapse and axon retraction of retinal ganglion cells could be induced by EPHB2 gene expression (53).…”

Section: Significancementioning

confidence: 99%

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Jin

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The etiology of the highly myopic condition has been unclear for decades. We investigated the genetic contributions to early-onset high myopia (EOHM), which is defined as having a refraction of less than or equal to −6 diopters before the age of 6, when children are less likely to be exposed to high educational pressures. Trios (two nonmyopic parents and one child) were examined to uncover pathogenic mutations using whole-exome sequencing. We identified parent-transmitted biallelic mutations or de novo mutations in asyet-unknown or reported genes in 16 probands. Interestingly, an increased rate of de novo mutations was identified in the EOHM patients. Among the newly identified candidate genes, a BSG mutation was identified in one EOHM proband. Expanded screening of 1,040 patients found an additional four mutations in the same gene. Then, we generated Bsg mutant mice to further elucidate the functional impact of this gene and observed typical myopic phenotypes, including an elongated axial length. Using a trio-based exonic screening study in EOHM, we deciphered a prominent role for de novo mutations in EOHM patients without myopic parents. The discovery of a disease gene, BSG, provides insights into myopic development and its etiology, which expands our current understanding of high myopia and might be useful for future treatment and prevention.early-onset high myopia | de novo mutations | BSG | rare inherited mutations

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Section: Significancementioning

confidence: 99%

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Jin

Huang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…We assessed the probability of pathogenicity of the variants found in the patients by analyzing the data from public databases, family analyses, and prediction algorithms 12,13 (Table 1; supplemental Table 2). …”

Section: Evaluation Of Pathogenicitymentioning

confidence: 99%

“…12,13 Different computational algorithms were used for prediction of the effect of MECOM mutations on protein function: PROVEAN (Protein Variation Effect Analyzer), 14 SIFT (Sorting Intolerant From Tolerant), 15 Polyphen2, 16 and MutationTaster. 17 …”

Section: Evaluation Of Pathogenicitymentioning

confidence: 99%

MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia

et al. 2018

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“…Recent studies [1, 4] suggests that a framework for organizing and communicating evidential support and the reasoning behind specific assessments of variant pathogenicity facilitates resolution of inter-laboratory discordances. However, currently available software systems and web services provide only rudimentary support for guideline-based reasoning [7] and do not facilitate full evidence tracking or collaborative resolution of discordances. They also do not enable guideline configuration to meet ACMG guideline specification and customization for specific genes and diseases, nor integration with existing variant curation systems.…”

Section: Introductionmentioning

confidence: 99%

ClinGen Pathogenicity Calculator: a configurable system for assessing pathogenicity of genetic variants

et al. 2017

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BackgroundThe success of the clinical use of sequencing based tests (from single gene to genomes) depends on the accuracy and consistency of variant interpretation. Aiming to improve the interpretation process through practice guidelines, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have published standards and guidelines for the interpretation of sequence variants. However, manual application of the guidelines is tedious and prone to human error. Web-based tools and software systems may not only address this problem but also document reasoning and supporting evidence, thus enabling transparency of evidence-based reasoning and resolution of discordant interpretations.ResultsIn this report, we describe the design, implementation, and initial testing of the Clinical Genome Resource (ClinGen) Pathogenicity Calculator, a configurable system and web service for the assessment of pathogenicity of Mendelian germline sequence variants. The system allows users to enter the applicable ACMG/AMP-style evidence tags for a specific allele with links to supporting data for each tag and generate guideline-based pathogenicity assessment for the allele. Through automation and comprehensive documentation of evidence codes, the system facilitates more accurate application of the ACMG/AMP guidelines, improves standardization in variant classification, and facilitates collaborative resolution of discordances. The rules of reasoning are configurable with gene-specific or disease-specific guideline variations (e.g. cardiomyopathy-specific frequency thresholds and functional assays). The software is modular, equipped with robust application program interfaces (APIs), and available under a free open source license and as a cloud-hosted web service, thus facilitating both stand-alone use and integration with existing variant curation and interpretation systems. The Pathogenicity Calculator is accessible at http://calculator.clinicalgenome.org.ConclusionsBy enabling evidence-based reasoning about the pathogenicity of genetic variants and by documenting supporting evidence, the Calculator contributes toward the creation of a knowledge commons and more accurate interpretation of sequence variants in research and clinical care.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0391-z) contains supplementary material, which is available to authorized users.

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An openly available online tool for implementing the ACMG/AMP standards and guidelines for the interpretation of sequence variants

Cited by 105 publications

References 2 publications

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

Trio-based exome sequencing arrests de novo mutations in early-onset high myopia

MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia

ClinGen Pathogenicity Calculator: a configurable system for assessing pathogenicity of genetic variants

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