Submissions for variant NM_000162.5(GCK):c.208+11G>A

gnomAD frequency: 0.00124  dbSNP: rs77440690

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195056	SCV000052524	benign	not specified	2024-05-02	criteria provided, single submitter	clinical testing	Variant summary: GCK c.208+11G>A alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 0.0016 in 251162 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 64 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.208+11G>A has been reported in the literature as a polymorphism and did not cosegregate with disease in at least one family (e.g. Pruhova_2003, Lehto_1999, Zouali_1993). 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, 12627330, 8349034, 15841481). ClinVar contains an entry for this variant (Variation ID: 36206). Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000195056	SCV000247463	likely benign	not specified	2018-10-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000029869	SCV000469448	benign	Maturity-onset diabetes of the young type 2	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000195056	SCV000719960	likely benign	not specified	2017-05-26	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.
Illumina Laboratory Services, Illumina	RCV001162365	SCV001324316	likely benign	Transient Neonatal Diabetes, Recessive	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001162366	SCV001324317	likely benign	Permanent neonatal diabetes mellitus	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001162367	SCV001324318	likely benign	Hyperinsulinism due to glucokinase deficiency	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Baylor Genetics	RCV001336705	SCV001530164	uncertain significance	Type 2 diabetes mellitus	2018-01-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV002054493	SCV002491808	benign	not provided	2023-11-17	criteria provided, single submitter	clinical testing