Submissions for variant NM_000162.5(GCK):c.649G>A (p.Asp217Asn)

gnomAD frequency: 0.00011  dbSNP: rs147065275

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003325990	SCV004032090	benign	Monogenic diabetes	2023-08-13	reviewed by expert panel	curation	The c.649G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 217 (p.(Asp217Asn)) of [transcript, e.g. NM_000545.8]. 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 in gnomAD 2.1.1 of 0.00005377, which is greater than the MDEP threshold for BS1 (≥0.0.00004) (BS1). This variant was identified in four 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). Additionally, this variant was identified in an individual with a normal fasting glucose (BS2) (internal lab contributor). This variant has been observed in cis with the variant GCK c.781G>A (p.Gly261Arg) (PMID:22611063), which is classified as pathogenic by the ClinGen MDEP (BP2). Lastly, functional studies suggest that the p.Asp217Asn protein has increased activity (RAI=2.0); however, the thermostability and protein interactions were not analyzed and therefore neither PS3 or BS3 can be applied (PMID 22611063). In summary, c.649G>A 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): BS1, BS2, BP2, PP2.
Illumina Laboratory Services, Illumina	RCV001164187	SCV001326294	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	RCV001164188	SCV001326295	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	RCV001164189	SCV001326296	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	RCV001164190	SCV001326297	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001315293	SCV001505862	uncertain significance	not provided	2023-05-19	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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GCK function (PMID: 22611063). 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: 911631). This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 22611063, 27913849). This variant is present in population databases (rs147065275, gnomAD 0.3%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 217 of the GCK protein (p.Asp217Asn).
New York Genome Center	RCV002468180	SCV002764596	uncertain significance	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2021-03-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004629472	SCV005126413	likely benign	Maturity onset diabetes mellitus in young	2024-06-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.