Submissions for variant NM_000162.5(GCK):c.1344del (p.Ala449fs)

dbSNP: rs1057524901

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV000445487	SCV004012130	pathogenic	Monogenic diabetes	2023-06-24	reviewed by expert panel	curation	The c.1344del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 449 (NM_000162.5), adding 165 novel amino acids before encountering a stop codon (p.(p.Ala449ArgfsTer165)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in five unrelated individuals with a clinical picture consistent with non-autoimmune/insulin-deficient diabetes (PS4_Moderate; ClinVar ID 393448, internal lab contributors). This variant segregated with disease, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies)(PP4_Moderate, internal lab contributor). In summary, the c.1344del variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PP1_Moderate, PP4_Moderate, PS4_Moderate, PM2_Supporting).
Translational Genomics Laboratory, University of Maryland School of Medicine	RCV000445487	SCV000537118	likely pathogenic	Monogenic diabetes	2015-06-12	criteria provided, single submitter	clinical testing	The c.1344delC variant in codon 448 (exon 10) of the GCK gene results in a frameshift in the protein sequence at codon 449, adding 164 novel amino acids before encountering a stop codon. Loss of function frameshift and nonsense mutations in exon 10 of the GCK gene have been reported previously in patients with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (19790256; 14517946; 19150152). In addition, the c.1344delC variant is not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; ACMG Criteria = PVS1, PM2
Invitae	RCV003565423	SCV004312408	pathogenic	not provided	2023-08-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GCK protein in which other variant(s) (p.Ser453Leu) have been determined to be pathogenic (PMID: 14517956, 16731834, 18399931). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 393448). This variant has not been reported in the literature in individuals affected with GCK-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the GCK gene (p.Ala449Argfs*165). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the GCK protein and extend the protein by 147 additional amino acid residues.