Submissions for variant NM_000162.5(GCK):c.1364T>A (p.Val455Glu)

gnomAD frequency: 0.00001  dbSNP: rs753795627

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000711767	SCV000842161	likely pathogenic	not provided	2024-09-05	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) In our internal patient population, this variant is statistically more frequent than in the general population, which is weak evidence this variant may be disease causing. This variant has been identified in at least one individual with clinical features associated with autosomal dominant maturity-onset diabetes of the young (MODY). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 18481947, 34532767)
CeGaT Center for Human Genetics Tuebingen	RCV000711767	SCV001155071	likely pathogenic	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711767	SCV002129033	uncertain significance	not provided	2024-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 455 of the GCK protein (p.Val455Glu). This variant is present in population databases (rs753795627, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical history consistent with GCK-related conditions (PMID: 19002431, 25555642, 31264968, 34789499, 36400171; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 585916). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GCK protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 18481947). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469275	SCV002765941	likely pathogenic	Maturity-onset diabetes of the young type 2	2025-01-07	criteria provided, single submitter	clinical testing	Variant summary: GCK c.1364T>A (p.Val455Glu) results in a non-conservative amino acid change located in the hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 238652 control chromosomes. c.1364T>A has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 2/Neonatal Diabetes Mellitus (e.g. Lukasova_2008, Gloyn_2009, Bennett_2015, Colclough_2022, Yu_2019). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function suggesting that the variant has an inactivating effect on the protein and reduces activity (e.g. Gloyn_2008, Langer_2021). The most pronounced variant effect results in 10%-<30% of normal activity (Gloyn_2008) consistent with the established molecular mechanism of disease. The following publications have been ascertained in the context of this evaluation (PMID: 34789499, 34532767, 31264968, 25555642, 19002431, 18481947, 18271687). ClinVar contains an entry for this variant (Variation ID: 585916). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV000711767	SCV003927524	likely pathogenic	not provided	2023-05-25	criteria provided, single submitter	clinical testing	Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18271687, 18481947, 31264968, 36400171, 36208030, 34789499, 19002431, 34662886, 34532767)
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000711767	SCV002035523	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000711767	SCV002037348	pathogenic	not provided		no assertion criteria provided	clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV003446380	SCV004174098	pathogenic	Maturity-onset diabetes of the young type 1		no assertion criteria provided	clinical testing