rs1057524901

chr7-44145189-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000162.5(GCK):c.1344del(p.Ala449ArgfsTer165) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: -2.28

Genes affected

GCK (HGNC:4195): (glucokinase) This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-44145189-CG-C is Pathogenic according to our data. Variant chr7-44145189-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 393448.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.1344del	p.Ala449ArgfsTer165	frameshift_variant	10/10	ENST00000403799.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.1344del	p.Ala449ArgfsTer165	frameshift_variant	10/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Jun 24, 2023	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Translational Genomics Laboratory, University of Maryland School of Medicine	Jun 12, 2015	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 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 05, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057524901; hg19: chr7-44184788;