7-44147690-G-C

Variant names:

• chr7-44147690-G-C
• NM_000162.5:c.823C>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_Moderate PM2_Supporting PP2 PP3 PP1_Strong PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The c.823C>G variant in the glucokinase gene, GCK, causes an amino acid change of arginine to glycine at codon 275 (p.(Arg275Gly)) of 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.792, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.823C>T p.Arg275Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg275Gly. In addition, the missense variant c.824G>T p.Arg275 Leu has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and 3 generation family history of diabetes) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with hyperglycemia with 8 informative meioses in 2 families (PP1_Strong; internal lab contributors). In summary, c.823C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367400479/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 5.35

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]

LOC105375258 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.823C>G	p.Arg275Gly	missense_variant	Exon 7 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.823C>G	p.Arg275Gly	missense_variant	Exon 7 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459898 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Jan 10, 2025

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.823C>G variant in the glucokinase gene, GCK, causes an amino acid change of arginine to glycine at codon 275 (p.(Arg275Gly)) of 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.792, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.823C>T p.Arg275Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg275Gly. In addition, the missense variant c.824G>T p.Arg275 Leu has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and 3 generation family history of diabetes) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with hyperglycemia with 8 informative meioses in 2 families (PP1_Strong; internal lab contributors). In summary, c.823C>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting. -

not specified Uncertain:1

Nov 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GCK c.823C>G (p.Arg275Gly) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250398 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.823C>G has been reported in the literature in settings of multigene panel testing in one proband from a cohort referred for Maturity Onset Diabetes of the Young genetic testing (example, Sain-Martin_2022). The specifc clinical criteria of GCK-associated Monogenic Diabetes is not explicitly specified. These report(s) do not provide unequivocal conclusions about association of the variant with Monogenic Diabetes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants located at the same codon, namely c.823C>T (p.Arg275Cys)/c.824G>T (p.Arg275Leu)/c.824G>C (p.Arg275Pro) have been classified as Pathogenic/Likely pathogenic by the Clingen MODY expert panel, supporting a critical relevance of this Arginine reside to GCK protein function. The following publication have been ascertained in the context of this evaluation (PMID: 34556497). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;.;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.2	.;M;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	.;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.026	.;D;D;D;D
Sift4G	Benign	0.078	T;T;T;T;T
Polyphen		0.93	P;P;P;B;.
Vest4		0.89
MutPred		0.61		.;Loss of stability (P = 0.0109);.;.;.;
MVP		0.95
MPC		2.4
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-44187289;