ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1358C>T (p.Ser453Leu)

dbSNP: rs193922283
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271378 SCV000052518 likely pathogenic Monogenic diabetes 2022-06-09 criteria provided, single submitter clinical testing Variant summary: GCK c.1358C>T (p.Ser453Leu) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 240536 control chromosomes (gnomAD). c.1358C>T has been reported in the literature in individuals affected with Monogenic Diabetes (examples: Sagen_2008 and Thomson_2003). These data indicate that the variant is likely to be associated with disease. Sagen et al (2006) have shown that this missense change affects GCK function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Athena Diagnostics Inc RCV000517061 SCV000613413 likely pathogenic not provided 2020-02-04 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Fulgent Genetics, Fulgent Genetics RCV000763582 SCV000894421 likely pathogenic Permanent neonatal diabetes mellitus; Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000517061 SCV002161526 pathogenic not provided 2021-11-30 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 14517956, 16731834, 18399931; Invitae). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 16731834). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 36200). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 453 of the GCK protein (p.Ser453Leu).
Geisinger Clinic, Geisinger Health System RCV002285258 SCV002562160 likely pathogenic Maturity-onset diabetes of the young type 2 2022-08-02 criteria provided, single submitter research PM2, PP3, PP1, PS4_Supporting, PM5_Supporting, PP4, PP2, PS3_Supporting

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