Submissions for variant NM_000162.5(GCK):c.491T>C (p.Leu164Pro)

dbSNP: rs2096278847

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293474	SCV001482047	pathogenic	Maturity-onset diabetes of the young type 2	2021-02-24	criteria provided, single submitter	clinical testing	Variant summary: GCK c.491T>C (p.Leu164Pro) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250018 control chromosomes. c.491T>C has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 2/Neonatal Diabetes Mellitus (e.g. Nam_2000, Garin_2008, Raimondo_2014, Szopa_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant results in reduced GCK enzyme activity and lower affinity for glucose and ATP (e.g. Raimondo_2014). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001871744	SCV002290851	uncertain significance	not provided	2022-11-09	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCK protein function. ClinVar contains an entry for this variant (Variation ID: 997861). This missense change has been observed in individuals with clinical features of maturity-onset diabetes of the young (PMID: 11106831, 18248649, 26552609; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 164 of the GCK protein (p.Leu164Pro). This variant disrupts the p.Leu164 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 30977832), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003127763	SCV002605225	likely pathogenic	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs2096278847 in MODY, yet.
Athena Diagnostics	RCV001871744	SCV002771534	likely pathogenic	not provided	2022-05-11	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with maturity-onset diabetes of the young (MODY). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
GeneDx	RCV001871744	SCV004035464	likely pathogenic	not provided	2023-03-13	criteria provided, single submitter	clinical testing	Published functional studies suggest this variant has severely reduced binding affinity for glucose or ATP (Raimondo et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 11106831, 25015100, 24918535, 18248649, 21981029, 26552609, 14517946)