Submissions for variant NM_000162.5(GCK):c.1285A>C (p.Arg429=)

gnomAD frequency: 0.00002  dbSNP: rs140672134

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003313032	SCV004012121	likely benign	Monogenic diabetes	2023-06-20	reviewed by expert panel	curation	The c.1285A>C variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 429 (p.(Arg429=)) of NM_000162.5. The Popmax filtering frequency of the c.1285A>C variant in gnomAD v2.1.1 is 0.000007310, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant is not predicted by SpliceAI to impact splicing (SpliceAI score less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.068, which is below the MDEP cutoff of 2.0) (BP4, BP7). This variant has been observed in unknown phase with the variant c.106C>T p.Arg36Trp, which is classified as likely pathogenic by the ClinGen MDEP (BP2). In summary, c.1285A>C meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2, approved 6/7/2023): BP2, BP4, BP7.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029855	SCV000052510	likely benign	Maturity-onset diabetes of the young type 2	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely benign.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002463430	SCV002604993	likely benign	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 rs140672134 in MODY, yet.