Submissions for variant NM_000162.5(GCK):c.1003del (p.Val335fs)

dbSNP: rs193922254

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317047	SCV000052484	pathogenic	Monogenic diabetes	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: GCK c.1003delG (p.Val335CysfsX18) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.1e-06 in 244148 control chromosomes. c.1003delG has been reported in the literature in individuals affected with features of Monogenic Diabetes (maturity-onset diabetes of the young, MODY) (example, Pihoker_2013, Alkorta-Aranburu_2014). The following publications have been ascertained in the context of this evaluation (PMID: 25306193, 23771925). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000255354	SCV000322347	pathogenic	not provided	2020-06-11	criteria provided, single submitter	clinical testing	Frameshift 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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23771925)
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000255354	SCV001448743	pathogenic	not provided	2018-07-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000255354	SCV002072045	pathogenic	not provided	2019-10-25	criteria provided, single submitter	clinical testing	DNA sequence analysis of the GCK gene demonstrated a single base pair deletion in exon 8, c.1003del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 17 amino acids downstream of the mutation, p.Val335Cysfs*18. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated GCK protein with potentially abnormal function. This pathogenic sequence change has previously been described in a patient with GCK-related hyperglycemia (PMID:23771925).
Ambry Genetics	RCV002390120	SCV002703346	pathogenic	Maturity onset diabetes mellitus in young	2023-03-20	criteria provided, single submitter	clinical testing	The c.1003delG pathogenic mutation, located in coding exon 8 of the GCK gene, results from a deletion of one nucleotide at nucleotide position 1003, causing a translational frameshift with a predicted alternate stop codon (p.V335Cfs*18). This mutation was identified in a cohort of individuals with non-gestational diabetes younger than age 20 years and with select negative diabetes autoantibodies (Pihoker C et al. J. Clin. Endocrinol. Metab., 2013 Oct;98:4055-62). 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.
Athena Diagnostics Inc	RCV000255354	SCV002771547	pathogenic	not provided	2021-11-23	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.
Invitae	RCV000255354	SCV004295147	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val335Cysfs*18) 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). This variant is present in population databases (rs193922254, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with diabetes (PMID: 23771925, 25306193). ClinVar contains an entry for this variant (Variation ID: 36166). For these reasons, this variant has been classified as Pathogenic.