rs1131691505

Positions:

• chr7-44145611-TGCGCAGCGC-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2_Supporting PM4

This summary comes from the ClinGen Evidence Repository: The c.1130_1138del variant in the glucokinase gene, GCK, is a 9 base pair deletion resulting in the in-frame deletion of 3 amino acids at codon 377 (p.(Arg377_Ala379del)) within exon 9 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The c.1130_1138del variant is predicted to change the length of the protein due an in-frame deletion of three amino acids in a non-repeat region (PM4). This variant segregated with hyperglycemia with two informative meioses in one family with MODY, which is below the threshold for PP1 (PMID:31063852). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMID 31063852, internal lab contributors). This variant was identified in an individual with hyperglycemia, however, PP4 is unable to be evaluated due to insufficient clinical information. In summary, this variant meets the criteria to be classified as uncertain significance for monogenic diabetes, ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA645369436/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 8.06

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]

GCK (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: 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.1130_1138delGCGCTGCGC	p.Arg377_Ala379del	disruptive_inframe_deletion	9/10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1130_1138delGCGCTGCGC	p.Arg377_Ala379del	disruptive_inframe_deletion	9/10	1	NM_000162.5	ENSP00000384247.3

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: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 19, 2017

- -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely pathogenic, 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 rs1131691505 in MODY, yet. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2017

The c.1130_1138delGCGCTGCGC variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This deletion results in the in-frame deletion of three amino acids; the deleted residues Arginine 377 and Alanine 378 are conserved across species, and Alanine 379 is conserved in mammals. Missense changes in the deleted residues (R377S/C/L/H, A378T/G/V/D, A379V/E) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Monogenic diabetes Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Feb 02, 2024

The c.1130_1138del variant in the glucokinase gene, GCK, is a 9 base pair deletion resulting in the in-frame deletion of 3 amino acids at codon 377 (p.(Arg377_Ala379del)) within exon 9 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The c.1130_1138del variant is predicted to change the length of the protein due an in-frame deletion of three amino acids in a non-repeat region (PM4). This variant segregated with hyperglycemia with two informative meioses in one family with MODY, which is below the threshold for PP1 (PMID: 31063852). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMID 31063852, internal lab contributors). This variant was identified in an individual with hyperglycemia, however, PP4 is unable to be evaluated due to insufficient clinical information. In summary, this variant meets the criteria to be classified as uncertain significance for monogenic diabetes, ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM4, PM2_Supporting. -

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: rs1131691505; hg19: chr7-44185210;