Submissions for variant NM_000162.5(GCK):c.1024A>C (p.Thr342Pro)

dbSNP: rs1000236360

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003493804	SCV004242356	benign	Monogenic diabetes	2024-02-02	reviewed by expert panel	curation	The c.1024A>C variant in the glucokinase gene, GCK, causes an amino acid change of threonine to proline at codon 342 (p.(Thr342Pro)) 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 Popmax filtering allele frequency of 0.000004789, which is between the MDEP thresholds for PM2_Supporting and BS1. This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 21604084, PMID: 33046911). However, this variant was identified in multiple individuals with a normal fasting glucose (BS2; PMID: 23799006, PMID 21604084). Additionally, this variant does not segregate with diabetes in one family in the literature (BS4; PMID: 21604084). This variant has a REVEL score of 0.296, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on GCK function. Additionally, functional studies are inconclusive on whether the p.Thr342Pro variant impacts glucokinase function (normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA interaction) (PMID 25015100). Two other missense variants, c.1024A>T (p.Thr342Ser) and c.1025C>T p.Thr342Met have been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. Taken together, the c.1024A>C variant meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): BS2, BS4, PP2.
Illumina Laboratory Services, Illumina	RCV001159192	SCV001320882	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	RCV001159193	SCV001320883	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.
Illumina Laboratory Services, Illumina	RCV001159194	SCV001320884	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	RCV001160541	SCV001322345	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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001159194	SCV001423015	uncertain significance	Maturity-onset diabetes of the young type 2	2020-01-22	criteria provided, single submitter	curation	The p.Thr342Pro variant in GCK has been reported in 3 individuals with maturity-onset diabetes of the young (PMID: 14517956, 21604084), and has been identified in 0.002% (2/110580) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1000236360). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The p.Thr342Pro variant did not segregate with maturity-onset diabetes of the young in 3 affected relatives of individuals from 2 families with the variant and was present in 5 unaffected relatives, suggesting that this variant is not pathogenic for maturity-onset diabetes of the young (PMID: 21604084). In summary, while the clinical significance of the p.Thr342Pro variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS4, BP4, PM2 (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV002483905	SCV002786520	uncertain significance	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2022-03-04	criteria provided, single submitter	clinical testing