Submissions for variant NM_000162.5(GCK):c.667G>A (p.Gly223Ser)

dbSNP: rs1360415315

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000502130	SCV000594959	pathogenic	Maturity-onset diabetes of the young type 2	2016-08-31	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000517681	SCV000613448	pathogenic	not provided	2023-08-24	criteria provided, single submitter	clinical testing	This variant segregates with disease in multiple families with clinical features of MODY (PMID: 21437567, 22291974, 22493702) and was also identified in one individual with PNDM (PMID: 26123671). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant reduces glucokinase activity (PMID: 22291974, 22493702).
Fulgent Genetics, Fulgent Genetics	RCV000763585	SCV000894424	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	RCV000517681	SCV002245936	pathogenic	not provided	2022-11-24	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects GCK function (PMID: 22291974, 22493702). 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. ClinVar contains an entry for this variant (Variation ID: 435306). This missense change has been observed in individuals with autosomal dominant GCK-related conditions (PMID: 21437567, 31216263, 32041611, 33294763, 33565752). It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 223 of the GCK protein (p.Gly223Ser).
GeneDx	RCV000517681	SCV002559475	pathogenic	not provided	2022-08-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate kinetic inactivation with a decreased rate of catalysis and reduced affinity for glucose (Garca-Herrero et al., 2012; Valentnov et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 22291974, 17573900, 16965331, 30663027, 31216263, 33294763, 33565752, 32041611, 28726111, 34789499, Mustafa_2019[Article], 34746319, 26123671, 22493702, 21437567, 11508276)
Ambry Genetics	RCV002367690	SCV002663328	pathogenic	Maturity onset diabetes mellitus in young	2017-05-17	criteria provided, single submitter	clinical testing	The p.G223S pathogenic mutation (also known as c.667G>A), located in coding exon 6 of the GCK gene, results from a G to A substitution at nucleotide position 667. The glycine at codon 223 is replaced by serine, an amino acid with similar properties. This mutation has been identified in numerous individuals ith maturity-onset diabetes of the young, segregating with disease (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26; Borowiec M et al. Acta Diabetol, 2011 Sep;48:203-8; Garc&iacute;a-Herrero CM et al. PLoS ONE, 2012 Jan;7:e30518; Valent&iacute;nov&aacute; L et al. PLoS ONE, 2012 Apr;7:e34541; Capuano M et al. PLoS ONE, 2012 Jun;7:e38906). This mutation was also identified in a compound heterozygous infant with persistent neonatal diabetes (Borowiec M et al. Acta Diabetol, 2011 Sep;48:203-8; Antosik K et al. Acta Diabetol, 2016 Apr;53:337-8). In addition, a GST fusion protein with this alteration expressed in E. coli demonstrated activity levels <10% of wild type with altered kinetics (Garc&iacute;a-Herrero CM et al. PLoS ONE, 2012 Jan;7:e30518). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403165	SCV004122238	pathogenic	Monogenic diabetes	2023-10-27	criteria provided, single submitter	clinical testing	Variant summary: GCK c.667G>A (p.Gly223Ser) 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 251410 control chromosomes (gnomAD). c.667G>A has been reported in the literature in multiple individuals affected with Maturity-onset diabetes of the young (Valentnov_2012, Garcia-Herrero_2012, Delvecchio_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and variant effect results in <10% of normal activity (Garcia-Herrero_2012). The following publications have been ascertained in the context of this evaluation (PMID: 11508276, 16965331, 17573900, 25414397, 22291974, 22493702). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.