Submissions for variant NM_000162.5(GCK):c.1340G>A (p.Arg447Gln)

dbSNP: rs1131691416

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494422	SCV000582084	likely pathogenic	not provided	2024-02-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 27271189, 19790256, 28012402, 14517946, 14517956, 28170077, 16965331, 22773699, 24097065, 24578721, 33046911, 32533152, 20337973, 34440516, 35472491, 36723869, 36504295, 35737141, 26587058, 36257325)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290675	SCV001478807	pathogenic	Maturity-onset diabetes of the young type 2	2021-01-27	criteria provided, single submitter	clinical testing	Variant summary: GCK c.1340G>A (p.Arg447Gln) results in a conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 241628 control chromosomes (gnomAD). c.1340G>A has been reported in the literature in multiple individuals with a suspected clinical diagnosis of or affected with Maturity Onset Diabetes of the Young 2 (example: Santana_2017, Flanick_2013, Vits_2006, Pruhova_2010, Thomson_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000494422	SCV002069076	likely pathogenic	not provided	2018-01-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000494422	SCV002771531	pathogenic	not provided	2022-08-16	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features associated with MODY. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
Fulgent Genetics, Fulgent Genetics	RCV002489206	SCV002802917	likely pathogenic	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2021-11-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000494422	SCV004295121	pathogenic	not provided	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 447 of the GCK protein (p.Arg447Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of maturity onset diabetes of the young (PMID: 14517956, 16965331, 20337973, 22773699, 28170077, 34023340, 34440516, 35472491, 36257325). ClinVar contains an entry for this variant (Variation ID: 429500). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function with a negative predictive value of 80%. This variant disrupts the p.Arg447 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26587058; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.