Submissions for variant NM_000162.5(GCK):c.1019+18G>A

gnomAD frequency: 0.00322  dbSNP: rs150914617

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000418514	SCV000513129	likely benign	not specified	2016-01-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Athena Diagnostics	RCV000711755	SCV000842149	benign	not provided	2017-08-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711755	SCV002404503	benign	not provided	2025-01-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002488878	SCV002799392	likely benign	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2022-04-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000418514	SCV004121941	benign	not specified	2023-10-03	criteria provided, single submitter	clinical testing	Variant summary: GCK c.1019+18G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Three computational tools predict that the variant abolishes a cryptic 5' splicing donor site but does not affect the canonical splice site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0032 in 239030 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 126-fold of the estimated maximal expected allele frequency for a pathogenic variant in GCK causing Monogenic Diabetes phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1019+18G>A has been reported in the literature in individuals affected with diabetes and hyperinsulinism without evidence of cosegregation with disease (e.g. Lehto_1999, Johansen_2005, Lukasova_2008, Odem_2009, Snider_2013). These reports do not provide unequivocal conclusions about association of the variant with Monogenic Diabetes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10447526, 14517946, 15928245, 18271687, 19515026, 23275527). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000711755	SCV004156831	likely benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	GCK: BP4
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000418514	SCV004848490	benign	not specified	2020-11-06	criteria provided, single submitter	clinical testing	The c.1016+18G>A variant in GCK classified as benign because it has been identified in 0.5% (660/125912) of European chromosomes, including 2 homozygote occurences, by gnomAD (http://gnomad.broadinstitute.org). In additon, it is not located within the splice consensus sequence and computational splice prediction tools predict disruption of a cryptic splice at this position without effect on the canonical splice. It has been reported in ClinVar (Variation ID: 377918). ACMG/AMP Criteria applied: BS1, BP4, BP7.
Breakthrough Genomics, Breakthrough Genomics	RCV000711755	SCV005227293	likely benign	not provided		criteria provided, single submitter	not provided