Submissions for variant NM_000162.5(GCK):c.10G>A (p.Asp4Asn)

gnomAD frequency: 0.00002  dbSNP: rs202091228

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003480976	SCV004223877	likely benign	Monogenic diabetes	2023-12-08	reviewed by expert panel	curation	The c.10G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 4 (p.(Asp4Asn)) 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 0.312, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function.The Popmax filtering allele frequency of the c.10G>A variant in gnomAD v2.1.1 is 0.00001687, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.00004); thus, neither criterion will be applied. This variant was identified in an individual with a normal fasting glucose and HbA1c less than or equal to 5.5% (BS2; internal lab contributors). This variant has been observed in unknown phase with the variant c.835G>T p.Glu279* (PMID: 8433729), which meets the criteria for as pathogenic by the ClinGen MDEP (BP2). In summary, c.10G>A 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): BS2, BP2, PP2.
Illumina Laboratory Services, Illumina	RCV001164411	SCV001326535	uncertain significance	Permanent neonatal diabetes mellitus	2017-04-28	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	RCV001164412	SCV001326536	uncertain significance	Hyperinsulinism due to glucokinase deficiency	2017-04-28	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	RCV001164413	SCV001326537	uncertain significance	Maturity-onset diabetes of the young type 2	2017-04-28	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	RCV001164414	SCV001326538	uncertain significance	Transient Neonatal Diabetes, Recessive	2017-04-28	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.
Fulgent Genetics, Fulgent Genetics	RCV002483920	SCV002779804	uncertain significance	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2022-01-27	criteria provided, single submitter	clinical testing
Invitae	RCV003558733	SCV004295194	uncertain significance	not provided	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 4 of the GCK protein (p.Asp4Asn). This variant is present in population databases (rs202091228, gnomAD 0.005%). This missense change has been observed in individual(s) with diabetes (PMID: 8433729, 11942313, 37008541). ClinVar contains an entry for this variant (Variation ID: 911766). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect GCK function (PMID: 8325892). 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.