Submissions for variant NM_000162.5(GCK):c.130G>A (p.Gly44Ser)

dbSNP: rs267601516

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000992045	SCV001144009	pathogenic	not provided	2021-05-28	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant segregates with disease in at least one family. Computational tools predict that this variant is damaging.
GeneDx	RCV000992045	SCV001823810	likely pathogenic	not provided	2021-03-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 32041611, 32533152, 22060211, 30245511, 33409956, 32375122, 19790256, 25555642, 29927023, 28726111, 17573900, 19309449, 22389783, 26226118, 24804978, 11692182, 14517956, 14517946, 21348868, 16092045, 30155490, 31638168, 31216263, 15580558)
Genetic Services Laboratory, University of Chicago	RCV000992045	SCV002072119	likely pathogenic	not provided	2021-08-04	criteria provided, single submitter	clinical testing	DNA sequence analysis of the GCK gene demonstrated a sequence change, c.130G>A, in exon 2 that results in an amino acid change, p.Gly44Ser. This sequence change has been reported in multiple individuals with MODY (PMID: 30245511, 33477506, 31968686, 19309449). This sequence change has not been described in population databases including EXAC and gnomAD. The p.Gly44Ser change affects a highly conserved amino acid residue located in a domain of the GCK protein that is known to be functional. The p.Gly44Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Gly44Ser amino acid change occurs in a region of the GCK gene where other missense sequence changes have been described in individuals with GCK-related MODY and different sequence changes affecting the same amino acid residue (p.Gly44Asp, p.Gly44Cys, Gly44Ala) have been reported in individuals with GCK-related disorders (PMID: 12627330, 19790256, 33409956). This sequence change is the likely cause of this individual's phenotype, however functional studies have not been performed to prove this conclusively.
Invitae	RCV000992045	SCV002232437	pathogenic	not provided	2023-06-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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 not expected to disrupt GCK protein function. ClinVar contains an entry for this variant (Variation ID: 76898). This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 11692182, 17573900, 24804978, 30245511, 31216263, 31638168). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 44 of the GCK protein (p.Gly44Ser).
Geisinger Clinic, Geisinger Health System	RCV002285265	SCV002562158	pathogenic	Maturity-onset diabetes of the young type 2	2022-08-02	criteria provided, single submitter	research	PM2, PP3, PP1_Strong, PS4, PM5, PP4, PP2