rs193929375

Positions:

• chr7-44145560-C-A
• chr7-44145560-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS3_Moderate PM2_Supporting PS4 PP1_Strong PP4_Moderate PM3 PP2 PP3

This summary comes from the ClinGen Evidence Repository: The c.1190G>T variant in the glucokinase gene, GCK, causes an amino acid change of Arg to Leu at codon 397 (p.(Arg397Leu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.925 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:17186219 , internal lab contributors). This variant segregated with diabetes, with at least 7 informative meioses in 14 families with MODY (PP1_Strong; 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, HbA1c 5.6 - 7.6%, and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:17186219). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Arg397Leu has RAI=0.72, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 17186219). This variant has been detected in the homozygous state in at least 5 individuals with neonatal diabetes (PM3; internal lab contributors). In summary, c.1190G>T 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): PM2_Supporting, PP2, PP3, PS4, PP1_Strong, PP4_Moderate, PS3_Supporting, PM3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA341587/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 6.10

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 Pathogenic. Variant got 17 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.1190G>T	p.Arg397Leu	missense_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.1190G>T	p.Arg397Leu	missense_variant	9/10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454950 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723526

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jul 16, 2023

The c.1190G>T variant in the glucokinase gene, GCK, causes an amino acid change of Arg to Leu at codon 397 (p.(Arg397Leu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.925 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:17186219 , internal lab contributors). This variant segregated with diabetes, with at least 7 informative meioses in 14 families with MODY (PP1_Strong; 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, HbA1c 5.6 - 7.6%, and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:17186219). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Arg397Leu has RAI=0.72, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 17186219). This variant has been detected in the homozygous state in at least 5 individuals with neonatal diabetes (PM3; internal lab contributors). In summary, c.1190G>T 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): PM2_Supporting, PP2, PP3, PS4, PP1_Strong, PP4_Moderate, PS3_Supporting, PM3. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 21, 2016

- -

Permanent neonatal diabetes mellitus Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;D;D;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;.;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;.;M;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.8	.;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	.;D;D;D;D;D
Sift4G	Uncertain	0.023	D;T;D;D;D;D
Polyphen		1.0	D;.;D;D;P;D
Vest4		0.71
MutPred		0.89		.;.;Loss of disorder (P = 0.0435);.;.;.;
MVP		0.96
MPC		2.5
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.95

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: rs193929375; hg19: chr7-44185159;