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 )

Dorzagliatin, a Dual-Acting Glucokinase Activator, Increases Insulin Secretion and Glucose Sensitivity in Glucokinase Maturity-Onset Diabetes of the Young and Recent-Onset Type 2 Diabetes

“…Participants with type 2 diabetes had the diagnosis for at least 3 months with <2 years with HbA 1c ≥6.5% (48 mmol/mol) and <8% (64 mmol/mol) for diet control and ≥6.0% (42 mmol/mol) and <8% (64 mmol/mol) for treatment with metformin. Participants with GCK-MODY had a fasting plasma glucose >5.6 mmol/L and were heterozygous carriers of a pathogenic or likely pathogenic GCK mutation at screening based on guidelines published by the American College of Medical Genetics and Genomics ( 8 ), Association for Clinical Genomic Science ( 9 ), and the ClinGen Monogenic Diabetes Expert Panel ( 10 ).…”

“…Pooled libraries were sequenced using a MiSeq instrument (Illumina, San Diego, CA) with paired-end run of 151 cycles, with FASTQ files as raw sequencing output per read. Sequencing variants that passed quality control were interpreted according to published guidelines ( 8 – 10 ).…”

Differences between transient neonatal diabetes mellitus subtypes can guide diagnosis and therapy

“…In addition, a patient carrying the ABCC8/H105Y variant has also been described here despite being a variant of uncertain significance according to the current ACMG criteria. Recently, gene-specific rules for variant interpretation are being developed by several Clin Gen Expert panels (46,47). Thus, we suggest that a long-lasting, positive response to sulfonylureas at diabetes relapse in a carrier of a K ATP variant might be incorporated among criteria indicating pathogenicity.…”

Genetic testing for misclassified monogenic diabetes in Māori and Pacific peoples in Aōtearoa New Zealand with early-onset type 2 diabetes

“…Pathogenicity of variants were classified according to the ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP guidelines ( 14 , 15 ). The guidelines classify genetic variants into 5 different categories: (B) benign, (LB) likely benign, (VUS) variant of uncertain significance, (LP) likely pathogenic, or (P) pathogenic.…”