rs1554334610

Positions:

• chr7-44145600-CCGAGCACATGTGCGCAG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1133_1149del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 378 (NM_000162.5), adding 75 novel amino acids before encountering a stop codon (p.(Ala378GlyfsTer75)). This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.1133_1149del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658655962/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 7.40

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 Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.1133_1149del	p.Ala378GlyfsTer75	frameshift_variant	9/10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1133_1149del	p.Ala378GlyfsTer75	frameshift_variant	9/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jan 22, 2024

The c.1133_1149del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 378 (NM_000162.5), adding 75 novel amino acids before encountering a stop codon (p.(Ala378GlyfsTer75)). This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.1133_1149del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 21, 2018

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -

Maturity onset diabetes mellitus in young Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet .However, there is no sufficient evidence to ascertain the significance of rs1554334610 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554334610; hg19: chr7-44185199;