Submissions for variant NM_000162.5(GCK):c.951C>G (p.His317Gln)

gnomAD frequency: 0.00001  dbSNP: rs1379908545

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516618	SCV000613470	uncertain significance	not provided	2020-12-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000516618	SCV001875150	likely pathogenic	not provided	2024-10-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing; in the absence of RNA/functional studies the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 36257325, 31063852)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000516618	SCV002107962	pathogenic	not provided	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 317 of the GCK protein (p.His317Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant maturity onset diabetes of the young (PMID: 31063852, 36257325; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447426). 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 not expected to disrupt GCK protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Geisinger Clinic, Geisinger Health System	RCV002285351	SCV002562201	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PM2, PP3, PP1_Moderate, PS4_Strong, PM5_Supporting, PP4, PP2
Fulgent Genetics, Fulgent Genetics	RCV002476041	SCV002789929	uncertain significance	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2024-05-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235263	SCV003934329	uncertain significance	not specified	2024-02-21	criteria provided, single submitter	clinical testing	Variant summary: GCK c.951C>G (p.His317Gln) results in a non-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 benign effect of the variant on protein function. The variant was absent in 247832 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.951C>G has been reported in the literature in individuals suspected of Monogenic Diabetes (examples: Sanyoura_2019 and Mirshahi_2022). At-least one of these reports classified the variant as VUS (Sanyoura_2019). 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: 36257325, 31063852). ClinVar contains an entry for this variant (Variation ID: 447426). Based on the evidence outlined above, the variant was classified as uncertain significance.