ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.391T>C (p.Ser131Pro)

dbSNP: rs104894010
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Geisinger Clinic, Geisinger Health System RCV000017518 SCV002562171 likely pathogenic Maturity-onset diabetes of the young type 2 2022-08-02 criteria provided, single submitter research PM2, PP1_Strong, PP4, PP2, PS3_Supporting
Labcorp Genetics (formerly Invitae), Labcorp RCV002513078 SCV003439967 likely pathogenic not provided 2023-06-13 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 not expected to disrupt GCK protein function. Experimental studies have shown that this missense change affects GCK function (PMID: 8325892, 8495817). ClinVar contains an entry for this variant (Variation ID: 16138). This missense change has been observed in individuals with maturity onset diabetes of the young (MODY) (PMID: 2555564, 8495817, 36257325; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 131 of the GCK protein (p.Ser131Pro). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV003147297 SCV003835244 likely pathogenic Type 2 diabetes mellitus 2022-07-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000017518 SCV003835349 likely pathogenic Maturity-onset diabetes of the young type 2 2022-07-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147298 SCV003835697 likely pathogenic Hyperinsulinism due to glucokinase deficiency 2022-07-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147299 SCV003836386 likely pathogenic Permanent neonatal diabetes mellitus 1 2022-07-01 criteria provided, single submitter clinical testing
OMIM RCV000017518 SCV000037790 pathogenic Maturity-onset diabetes of the young type 2 1993-06-01 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV004730847 SCV005337665 likely pathogenic GCK-related disorder 2024-05-02 no assertion criteria provided clinical testing The GCK c.391T>C variant is predicted to result in the amino acid substitution p.Ser131Pro. This variant has been reported in an individual with gestational diabetes mellitus (Stoffel et al. 1993. PubMed ID: 8495817) and in individuals with mature onset diabetes of the young (MODY) (Bennett et al. 2014. PubMed ID: 25555642; Table S2, Mirshahi et al. 2022. PubMed ID: 36257325). In vitro functional studies using site directed mutagenesis with recombinant human B-cells show decreased enzyme activity and marked increase in glucose affinity (Takeda et al. 1993. PubMed ID: 8325892). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.

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