7-44145617-G-T

Variant names:

• chr7-44145617-G-T
• rs193929374
• NM_000162.5:c.1133C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP2 PP3 PM2_Supporting PP4_Moderate PM5_Strong PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1133C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to aspartic acid at codon 378 (p.(Ala378Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.984, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5-6 unrelated individuals with hyperglycemia (PS4; internal lab contributors). The variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mol/L and HbA1c 5.6-7.6% and three-generation, dominant family history of diabetes or hyperglycemia (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). Two other missense variants, c.1133C>T (p.Ala378Val) and c.1132G>A (p.Ala378Thr) have been interpreted as pathogenic by the ClinGen MDEP, and p.Ala378Asp has an greater Grantham distance than p.Ala378Val and p.Ala378Thr (PM5_Strong). In summary, this variant meets the criteria to be classified as pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PS4_moderate, PM5_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367398804/MONDO:0007453/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 8.06
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• hyperinsulinism due to glucokinase deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• maturity-onset diabetes of the young type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• transient neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300758 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.1133C>A	p.Ala378Asp	missense_variant	Exon 9 of 10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1133C>A	p.Ala378Asp	missense_variant	Exon 9 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Maturity-onset diabetes of the young type 2 Pathogenic:1

Nov 22, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1133C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to aspartic acid at codon 378 (p.(Ala378Asp)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.984, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5-6 unrelated individuals with hyperglycemia (PS4; internal lab contributors). The variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mol/L and HbA1c 5.6-7.6% and three-generation, dominant family history of diabetes or hyperglycemia (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). Two other missense variants, c.1133C>T (p.Ala378Val) and c.1132G>A (p.Ala378Thr) have been interpreted as pathogenic by the ClinGen MDEP, and p.Ala378Asp has an greater Grantham distance than p.Ala378Val and p.Ala378Thr (PM5_Strong). In summary, this variant meets the criteria to be classified as pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PS4_moderate, PM5_Strong. -

Monogenic diabetes Pathogenic:1

Nov 07, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GCK c.1133C>A (p.Ala378Asp) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Other variants located at the same codon, namely c.1133C>G (p.Ala378Gly); c.1133C>T (p.Ala378Val); c.1132C>A (p.Ala378Thr) have been reported with P/LP classifications, supporting a critical relevance of this Alanine residue to GCK protein function. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 234946 control chromosomes. c.1133C>A has been reported in the literature in individuals affected with features and clinical criteria of GCK-associated Monogenic Diabetes (example, Colclough_2022, Saint-Martin_2022, Mirshahi_2022, Osbak_2009). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34789499, 36257325, 19790256, 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 pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D;D;.;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	.;.;H;.;.;.
PhyloP100		8.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.9	.;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.99	D;.;D;D;D;D
Vest4		0.95
MutPred		0.98		.;.;Loss of MoRF binding (P = 0.0457);.;.;.;
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs193929374; hg19: chr7-44185216;