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

Abstract

Abbreviations GCK Glucokinase SNP Single nucleotide polymorphismTo 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 [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. Electronic supplementary material The online version of this article

Recognition and Management of Individuals With Hyperglycemia Because of a Heterozygous Glucokinase Mutation

“…These studies have provided important insights into the structure and regulation of glucokinase and can provide additional confidence in the interpretation of the significance of a genetic variant in glucokinase (72). (Table 2 and Fig.…”

When is it MODY? Challenges in the Interpretation of Sequence Variants in MODY Genes

“…Steele and colleagues found that a heterozygous GCK missense variant, p.T342P, which was previously reported as pathogenic loss-of-function, neither demonstrated impaired catalytic activity nor cosegregation with the disease phenotype in the two families in which it was identified [95]. The variant was also classified as benign by three different in silico prediction tools, SIFT, Polyphen, and Mutation Taster [95]. The p.T342P substitution was not inherited by relatives with an overtly diabetic or elevated fasting glucose phenotype, and other relatives in whom the allele was identified were euglycemic (<5.5 mmol/l fasting glucose) [95].…”

“…Transparent reporting of findings is equally pivotal, as this allows medics and researchers to make independent interpretations and assessments of the published data and the way in which they were generated. Recent familial/functional studies on glucokinase have shown that analyzing variants, which were previously reported and characterized as pathogenic in this combinatorial manner, sometimes showed the opposite effect [94,95]. Steele and colleagues found that a heterozygous GCK missense variant, p.T342P, which was previously reported as pathogenic loss-of-function, neither demonstrated impaired catalytic activity nor cosegregation with the disease phenotype in the two families in which it was identified [95].…”

“…Recent familial/functional studies on glucokinase have shown that analyzing variants, which were previously reported and characterized as pathogenic in this combinatorial manner, sometimes showed the opposite effect [94,95]. Steele and colleagues found that a heterozygous GCK missense variant, p.T342P, which was previously reported as pathogenic loss-of-function, neither demonstrated impaired catalytic activity nor cosegregation with the disease phenotype in the two families in which it was identified [95]. The variant was also classified as benign by three different in silico prediction tools, SIFT, Polyphen, and Mutation Taster [95].…”

Clinical utility gene card for: Maturity-onset diabetes of the young

“…13 Benign, non-pathogenic sequence variants can be reported as MODY causing mutations and careful interpretation taking into account functional studies, segregation analysis, in silico predictions and frequencies according to geographic origin of the patients is required. 22 …”