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

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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	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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