ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.483G>A (p.Lys161=)

dbSNP: rs193922302
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003234538 SCV003932645 pathogenic Monogenic diabetes 2023-05-26 reviewed by expert panel curation The c.483G>A variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 161 (p.(Lys161=)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). It is predicted by SpliceAI to impact splicing (SpliceAI score of 0.85 for donor gain and 0.52 for donor loss, which are greater than the MDEP cutoff of 0.2) (PP3), and there is evidence from RNA studies that this variant results in aberrant splicing, indicating that this variant impacts protein function (PS3; Internal lab contributor). This variant was identified in five unrelated individuals with mildly elevated HbA1c that did not require treatment, and segregated with the phenotype, with four informative meioses in three families (PS4_Moderate, PP1_Strong; PMID: 1956454, Internal lab contributors). In summary, c.483G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 3/23/23): PM2_Supporting, PP3, PS4_Moderate, PP1_Strong, PS3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029887 SCV000052542 likely pathogenic Maturity-onset diabetes of the young type 2 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002464001 SCV002605242 likely risk allele Maturity onset diabetes mellitus in young criteria provided, single submitter research Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs193922302 in MODY, yet.
Athena Diagnostics Inc RCV003482231 SCV004229663 pathogenic not provided 2023-08-29 criteria provided, single submitter clinical testing This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to segregate with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (Personal communication related to ClinVar ID: 36224, Accession: SCV003932645.1)

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