Sherloc: a comprehensive refinement of the ACMG–AMP variant classification criteria

Abstract

PurposeThe 2015 American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG–AMP) guidelines were a major step toward establishing a common framework for variant classification. In practice, however, several aspects of the guidelines lack specificity, are subject to varied interpretations, or fail to capture relevant aspects of clinical molecular genetics. A simple implementation of the guidelines in their current form is insufficient for consistent and comprehensive variant classification.MethodsWe undertook an iterative process of refining the ACMG–AMP guidelines. We used the guidelines to classify more than 40,000 clinically observed variants, assessed the outcome, and refined the classification criteria to capture exceptions and edge cases. During this process, the criteria evolved through eight major and minor revisions.ResultsOur implementation: (i) separated ambiguous ACMG–AMP criteria into a set of discrete but related rules with refined weights; (ii) grouped certain criteria to protect against the overcounting of conceptually related evidence; and (iii) replaced the “clinical criteria” style of the guidelines with additive, semiquantitative criteria.ConclusionSherloc builds on the strong framework of 33 rules established by the ACMG–AMP guidelines and introduces 108 detailed refinements, which support a more consistent and transparent approach to variant classification.

Novel data on growth phenotype and causative genotypes in 29 patients with Morquio (Morquio-Brailsford) syndrome from Central-Eastern Europe

“…This variant was reported previously as a mutation causing MPSIVA (HGMD Accession CM970588, ClinVar RCV000633457.1) by Bunge et al (1997) and Nykamp et al (2017). It was also annotated in ExAC database with MAF = 0.000016.…”

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“…24 Clinical reports included variants classified as pathogenic or likely This column shows curation of genes associated with biochemical disorders, genes for which pathogenic variants point to contraindications for certain anti-epileptic drugs (AEDs), and genes with indications for specific types of AEDs. Interpretation of observed variants in epilepsy genes was performed as described previously.…”

Factor VIII and vWF deficiency in STT3A‐CDG

“…This provides a mechanistic explanation for our patient's chronically low FVIII levels and activity (Figures , and ). Our findings provide first evidence of the likely pathogenicity of the novel variant c.1079A>C (p.Tyr360Ser) in STT3A . Patients with STT3A‐CDG may have a predisposition for coagulopathy due to aberrant N‐glycosylation that may be distinct from patients with other CDGs.…”