ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1322C>T (p.Ser441Leu)

dbSNP: rs1286804191
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003313087 SCV004012135 uncertain significance Monogenic diabetes 2023-06-25 reviewed by expert panel curation The c.1322C>T variant in the glucokinase gene, GCK, causes an amino acid change of glycine to asparagine at codon 441 (p.(Ser441Leu)) of NM_000162.5. This variant has a non-calculable Popmax filtering allele frequency, with absence in the gnomAD v2.1.1 European non-Finnish population and one copy in the African/African American subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). The variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.984, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 28726111). Another missense variant, c.1322C>G p.(Ser441Trp), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.(Ser441Leu) (PM5_Supporting). In summary, c.1322C>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP3, PP2, PP4, PM5_Supporting.
Genetic Services Laboratory, University of Chicago RCV000499850 SCV000594946 likely pathogenic Maturity-onset diabetes of the young type 2 2016-10-13 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV003482262 SCV000613412 uncertain significance not provided 2024-01-02 criteria provided, single submitter clinical testing Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with MODY and at least one individual with permanent neonatal diabetes mellitus. One other missense mutation found at the same codon position is classified as pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 37101203)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000499850 SCV001572380 likely pathogenic Maturity-onset diabetes of the young type 2 2021-04-01 criteria provided, single submitter clinical testing Variant summary: GCK c.1322C>T (p.Ser441Leu) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 243630 control chromosomes (gnomAD). c.1322C>T has been reported in the literature as homozygous occurrence in at least one individual affected with Permanent Neonatal Diabetes Mellitus (e.g. Flanagan_2014, Raimondo_2014) and as heterozygous occurrence in one family with clinical features of Maturity Onset Diabetes Of The Young (Aloi_2017). These data indicate that the variant may be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to confer decreased enzyme activity and thermostability (Raimondo_2014). One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Geisinger Clinic, Geisinger Health System RCV000499850 SCV002562159 likely pathogenic Maturity-onset diabetes of the young type 2 2022-08-02 criteria provided, single submitter research PM2, PP3, PP2, PP4, PM5_Supporting

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