ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.944T>A (p.Leu315His)

dbSNP: rs193922338
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029929 SCV000052584 pathogenic Maturity-onset diabetes of the young type 2 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago RCV001818187 SCV002067347 pathogenic not provided 2019-07-11 criteria provided, single submitter clinical testing DNA sequence analysis of the GCK gene demonstrated a sequence change, c.944T>A, in exon 8 that results in an amino acid change, p.Leu315His. This sequence change has been previously described in patients with GCK-related MODY in multiple unrelated family members and is one of the one of the most prevalent GCK mutations in the Czech population (PMIDs: 20337973, 22332836, 17204055). The p.Leu315His change affects a highly conserved amino acid residue located in a functional domain of the GCK protein that is known to be functional and other pathogenic variants have been described in this region. The p.Leu315His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies for this sequence change showed a severe loss of glucokinase activity (PMID: 26208450).
Invitae RCV001818187 SCV003439944 pathogenic not provided 2022-08-02 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 36266). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 16602010, 17204055, 22332836, 26552609). 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 leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 315 of the GCK protein (p.Leu315His). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 22493702, 26208450).

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