Submissions for variant NM_000162.5(GCK):c.1386G>T (p.Met462Ile)

gnomAD frequency: 0.00001  dbSNP: rs193922285

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003325947	SCV004032106	likely benign	Monogenic diabetes	2023-09-01	reviewed by expert panel	curation	The c.1386G>T variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 462 (p.(Met462Ile)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a REVEL score of 0.45, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). This variant was identified in at least 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (internal lab contributors). This variant was identified in at least two individuals with a normal fasting glucose (BS2) (PMID: 24097065). The Popmax filtering allele frequency of the c.1386G>T variant in gnomAD v2.1.1 is 0.00001159, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.00004); thus, neither criterion will be applied. Lastly, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1386G>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, BP5, BS2.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029865	SCV000052520	uncertain significance	not specified	2019-01-24	criteria provided, single submitter	clinical testing	Variant summary: The variant, GCK c.1386G>T (p.Met462Ile) results in a conservative amino acid change located in the Hexokinase, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The ExAC z score of 4.39 for this gene is indicative of it being relatively intolerant to benign missense variation. The variant allele was found at a frequency of 2.1e-05 in 237788 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1386G>T has been reported in the literature in at-least two individuals affected with MODY or Type 2 Diabetes (Maturity-onset diabetes of the young, type 2, Osbak_2009, Framingham Heart Study cohort, Flannick_2013). These reports however, does not provide unequivocal conclusions about association of the variant with MODY2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. As summarized above, at-least two new reports indicating its presence in individuals diagnosed with MODY2 or a related diabetic phenotype have emerged since its original classification.Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Athena Diagnostics	RCV000711768	SCV000842162	uncertain significance	not provided	2018-05-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001162069	SCV001324000	uncertain significance	Hyperinsulinism due to glucokinase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001162070	SCV001324001	uncertain significance	Maturity-onset diabetes of the young type 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001162071	SCV001324002	uncertain significance	Transient Neonatal Diabetes, Recessive	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001162072	SCV001324003	uncertain significance	Permanent neonatal diabetes mellitus	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001162070	SCV001422602	uncertain significance	Maturity-onset diabetes of the young type 2	2020-01-22	criteria provided, single submitter	curation	The p.Met462Ile variant in GCK has not been previously reported in individuals with maturity-onset diabetes of the young (MODY) type 2 but has been identified in 0.004028% (5/124138) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922285). This variant has also been reported in ClinVar (VariationID: 36202) as a VUS by Athena Diagnostics Inc and as likely pathogenic by Integrated Genetics; the former lab also reported one individual with the variant and MODY type 2. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Met462Ile variant is uncertain. ACMG/AMP Criteria applied: BS1 (Richards 2015).
GeneDx	RCV000711768	SCV001986062	uncertain significance	not provided	2019-10-08	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an unaffected individual from a large screening of MODY variants, and observed in one family with MODY, however, detailed phenotypic data is not available (Flannick et al., 2013; Osbak et al., 2009); This variant is associated with the following publications: (PMID: 24097065, 19790256)
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002463596	SCV002605045	uncertain 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 rs193922285 in MODY, yet.
Fulgent Genetics, Fulgent Genetics	RCV002496452	SCV002812338	uncertain significance	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2021-08-13	criteria provided, single submitter	clinical testing