Submissions for variant NM_000162.5(GCK):c.660C>A (p.Cys220Ter)

dbSNP: rs142952813

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003399324	SCV004102850	pathogenic	Monogenic diabetes	2023-10-13	reviewed by expert panel	curation	The c.660C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 220 (p.(Cys220Ter)) of NM_000162.5. This variant, located in exon 6 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 9790256). This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in multiple families (PP1_Strong; internal lab contributors). This variant was identified in at least 11 unrelated individuals with hyperglycemia (PS4; PMIDs: 21348868, 3347750, 31638168, 20337973, 12627330, 16602010, internal lab contributors. This variant was identified in at least 2 individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.660C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PVS1, PP1_Strong, PS4, PP4, PM2_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001527032	SCV001737854	pathogenic	Maturity-onset diabetes of the young type 2	2021-05-26	criteria provided, single submitter	clinical testing	Variant summary: GCK c.660C>A (p.Cys220X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251428 control chromosomes. c.660C>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 2 (Ziemssen_2002, Pruhova_2010). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics	RCV001658238	SCV001880736	pathogenic	not provided	2023-09-05	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant has been identified in multiple unrelated individuals with clinical features of MODY. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Geisinger Clinic, Geisinger Health System	RCV001527032	SCV002562187	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PVS1, PM2, PS4, PP1_Strong
GeneDx	RCV001658238	SCV002567552	pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33852230, 26641800, 25525159, 11942313, 31638168, 20337973, 26552609)
Ambry Genetics	RCV002368554	SCV002663450	pathogenic	Maturity onset diabetes mellitus in young	2021-01-07	criteria provided, single submitter	clinical testing	The p.C220* pathogenic mutation (also known as c.660C>A), located in coding exon 6 of the GCK gene, results from a C to A substitution at nucleotide position 660. This changes the amino acid from a cysteine to a stop codon within coding exon 6. This alteration has been reported in multiple individuals with a personal and family history consistent with MODY (Pruhova S et al. Diabetologia, 2003 Feb;46:291-5; Szopa M et al. Pol Arch Med Wewn, 2015 Nov;125:845-51; Glotov OS et al. Mol Med Rep, 2019 Dec;20:4905-4914). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002488347	SCV002801465	likely pathogenic	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2021-12-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001658238	SCV004295170	pathogenic	not provided	2022-12-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1172896). This premature translational stop signal has been observed in individual(s) with clinical features of GCK-related conditions (PMID: 11942313, 26641800, 31638168, 33852230). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys220*) in the GCK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCK are known to be pathogenic (PMID: 7553875, 9867845, 14578306, 24323243, 25015100).