ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.554T>G (p.Leu185Arg)

dbSNP: rs1583599749
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000992054 SCV001144022 uncertain significance not provided 2019-06-18 criteria provided, single submitter clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002346196 SCV002605217 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 rs1583599749 in MODY, yet.
Ambry Genetics RCV002346196 SCV002654032 likely pathogenic Maturity onset diabetes mellitus in young 2024-04-03 criteria provided, single submitter clinical testing The p.L185R variant (also known as c.554T>G), located in coding exon 5 of the GCK gene, results from a T to G substitution at nucleotide position 554. The leucine at codon 185 is replaced by arginine, an amino acid with dissimilar properties. This variant was reported in an individual with features consistent with maturity-onset diabetes of the young (MODY) (Sanyoura M et al. Diabetes Res Clin Pract, 2019 May;151:231-236; external communication). The variant also co-segregated with disease in affected family members (Ambry internal data). In an assay testing GCK function, this variant showed a functionally abnormal result (Gersing S et al. Genome Biol, 2023 Apr;24:97). Based on internal structural analysis, the variant is more disruptive to the structure of GCK than several nearby internally pathogenic variants (Kamata K et al. Structure, 2004 Mar;12:429-38).(Shi Y et al. J Med Chem, 2022 Mar;65:4291-4317). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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