Submissions for variant NM_000162.5(GCK):c.397T>C (p.Phe133Leu)

dbSNP: rs2128822093

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV001391314	SCV001593278	likely pathogenic	Maturity onset diabetes mellitus in young	2020-09-10	criteria provided, single submitter	clinical testing	This variant substitutes the phenylalanine with leucine at amino acid position 133. This is an evolutionary conserved position and in silico tools predict this alteration is damaging to protein function (DANN, FATHMM-MKL, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT). The p.Phe133Leu variant has previously been reported by our laboratory as a likely pathogenic change in an individual with MODY (PMID: 25555642). This variant has not been observed in the Genome Aggregation Database (v2.1.1).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844289	SCV002103380	uncertain significance	not specified	2022-02-25	criteria provided, single submitter	clinical testing	Variant summary: GCK c.397T>C (p.Phe133Leu) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. A different nucleotide change, c.398T>A (p.Phe133Tyr) affecting the same location has also been reported with an associated phenotype of MODY2 in the HGMD database supporting the functional relevance of this residue to overall protein function. The variant was absent in 251362 control chromosomes. c.397T>C has been reported in the literature as a likely pathogenic variant in at-least one individual reportedly affected with Maturity Onset Diabetes Of The Young in a referral laboratory cohort (example, Bennett_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The same clinical diagnostic laboratory reporting this variant has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003558829	SCV004295181	uncertain significance	not provided	2023-06-15	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Phe133 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 25555642, 33565752; Invitae), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function. ClinVar contains an entry for this variant (Variation ID: 1077171). This missense change has been observed in individual(s) with GCK-related conditions (PMID: 25555642). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 133 of the GCK protein (p.Phe133Leu).