ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.367T>C (p.Phe123Leu)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV003151529 SCV005388325 uncertain significance not provided 2024-03-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago RCV003151529 SCV003839554 likely pathogenic not provided 2022-06-16 no assertion criteria provided clinical testing DNA sequence analysis of the GCK gene demonstrated a sequence change, c.367T>C, in exon 4 that results in an amino acid change, p.Phe123Leu. The p.Phe123Leu change affects a highly conserved amino acid residue located in a domain of the GCK protein that is known to be functional. The p.Phe123Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This amino acid change, p.Phe123Leu, caused by a different nucleotide change, c.369C>G, has been reported in a child with MODY (PMID: 18382660). Additionally, a different pathogenic sequence change affecting the same amino acid residue (p.Phe123Ser) has been described in an individual with MODY and their similarly affected mother (PMID: 27256595) and this amino acid change occurs in a region of the GCK gene where other missense sequence changes have been described in individuals with MODY (PMID: 31063852, 32533152). This sequence change has not been described in population databases such as ExAC and gnomAD. This sequence change is the likely cause of this individual's phenotype, however functional studies have not been performed to prove this conclusively.

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