The previously reported T342P GCK missense variant is not a pathogenic mutation causing MODY


To the Editor: There is renewed interest in the difficulties of interpreting the role of missense variants identified in large scale medical resequencing projects made possible by next generation sequencing technologies. To assist in ascribing a role in disease causation for these variants, a combination of statistics, bioinformatic tools and, ultimately, functional studies, will be needed. Missense variants identified in highly penetrant Mendelian disorders where co-segregation studies can be performed provide a model to explore the utility of these tools. The glycolytic enzyme glucokinase plays a key role in glucose stimulated insulin secretion and has been termed the pancreatic beta cell glucose sensor [1]. Heterozygous inactivating mutations in the GCK gene encoding glucokinase cause a subtype of MODY characterised by mild fasting hyperglycaemia (fasting plasma glucose 5.5–8 mmol/l, HbA1c ≤7.5% [58 mmol/mol]) [2]. Over 600 different missense, nonsense, frameshift and splice site GCK mutations have been reported in patients with glucokinase (GCK)-MODY (dominant inactivating mutations), GCKPNDM (permanent neonatal diabetes; recessive inactivating mutations) or GCK-HH (hyperinsulinaemic hypoglycaemia; dominant activating mutations) and are reviewed by Osbak and colleagues [3]. Of the mutations in this recent review, the majority are missense (402/620 [65%]) and most of these (392/402 [97%]) are inactivating mutations causing hyperglycaemia. A preponderance of missense mutations (224/402 [56%]) have only been reported in a single family [3]. Surprisingly, of the 29 single nucleotide polymorphisms (SNPs) described within the coding region of the pancreatic isoform, only one (D4N) results in a missense substitution [3]. T342P (c.1024A>C; p.Thr342Pro) has previously been reported as a pathogenic mutation following its identification in a single family (family SQ) [4]. We now report a second, unrelated family (family GB) with this variant and our clinical and functional studies suggest that T342P should be re-classified as a rare, non-pathogenic variant. A. L. Gloyn and S. Ellard contributed equally to this study.

DOI: 10.1007/s00125-011-2194-5

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@article{Steele2011ThePR, title={The previously reported T342P GCK missense variant is not a pathogenic mutation causing MODY}, author={Andrea Steele and Nicolas D. Tribble and Robert Caswell and Kirsty J. Wensley and Andrew T Hattersley and Anna L . Gloyn and Sian Ellard}, journal={Diabetologia}, year={2011}, volume={54}, pages={2202-2205} }