1453-P: Adaption of the ACMG/AMP Variant Interpretation Guidelines for GCK, HNF1A, HNF4A-MODY: Recommendations from the ClinGen Monogenic Diabetes Expert Panel

Abstract

Genetic testing for monogenic diabetes, essential for accurate diagnosis and appropriate treatment is underutilized. Obstacles include clinical overlap with type 1 and type 2 diabetes and difficulty distinguishing clinically significant (pathogenic/likely pathogenic; P/LP) from normal (benign/likely benign; B/LB) variation. The ClinGen Monogenic Diabetes Expert Panel (MDEP) was formed to adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to monogenic diabetes genes and enable depositing of expert panel variant reviews into ClinVar, a public database relating gene variants to phenotypes. MDEP includes endocrinologists, laboratory directors, genetic counselors, medical geneticists, clinical scientists and researchers from 37 academic and commercial institutions, allowing the panel to benefit from multiple expert perspectives and pooling of case-level data. Currently, MDEP is focusing on the three most commonly implicated monogenic diabetes genes: GCK, HNF1A and HNF4A. MDEP generated gene-specific modifications and/or strength adjustments to existing rules to provide guidance for the use of evidence, including molecular, phenotypic, segregation, functional, and minor allele frequency data. Our guidelines have so far been tested on 98 HNF1A variants, 15 HNF4A variants and 22 GCK variants selected from ClinVar and the literature. Fourteen of 31 variants of uncertain significance (VUS) in ClinVar were re-classified: nine to P/LP (enabling diagnosis and treatment) and five to B/LB (reducing ambiguity). Six LP variants and one LB variant from ClinVar were re-classified to VUS (stimulating further surveillance). MDEP’s work will improve accuracy, standardization and concordance of variant interpretation for monogenic diabetes and support wider implementation of precision medicine in diabetes. Disclosure H. Zhang: None. K.A. Maloney: None. F. Barbetti: Consultant; Self; Amring. S.W. Greeley: None. J.L.T. Kettunen: None. J.P. Miranda: None. U.L. Mirshahi: None. J. Molnes: None. R. Murphy: None. R.N. Naylor: None. R.E. Pakyz: None. L.H. Philipson: None. S. Prudente: None. T. Tuomi: None. M. Udler: None. K. Colclough: None. L. Jeng: None. T.I. Pollin: None. Funding National Institutes of Health (5U24HD093486, R01DK104942, P30DK020595 )