rs193929373

Variant names:

• chr7-44147723-C-T
• rs193929373
• NM_000162.5:c.790G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PP2 PP3 PM2_Supporting PP4_Moderate PS4 PM3_Strong PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.790G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to serine at codon 264 (p.(Gly264Ser)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID:11508276, internal lab contributors). 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) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; PMID:16026363s, internal lab contributors). This variant has been detected in two individuals with neonatal diabetes. Both were compound heterozygous (confirmed in trans) for this variant and another variant classified as pathogenic by ClinGen MDEP (PM3_Strong; PMIDs: 14578306, 16026363, internal lab contributors). 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 0.847, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The Relative Activity Index (RAI) of this variant was found to be above the MDEP cutoff (0.5) for PS3_Moderate. While the p.Gly264Ser variant has been reported to cause protein misfolding, this is not considered to meet criteria for applying PS3_Supporting by the ClinGen MDEP (PMIDs: 22820548, 14578306, 16731834, https://doi.org/10.1159/000079009). In summary, c.790G>A 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, PS4, PP4_Moderate, PM3_Strong, PP2, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA341589/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 6.06
• Publications: 18 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

LOC105375258 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 17 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.
• 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 rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.790G>A	p.Gly264Ser	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.790G>A	p.Gly264Ser	missense_variant	Exon 7 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Nov 02, 2023

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.790G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to serine at codon 264 (p.(Gly264Ser)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 11508276, internal lab contributors). 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) (PP4_Moderate, internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; PMID: 16026363s, internal lab contributors). This variant has been detected in two individuals with neonatal diabetes. Both were compound heterozygous (confirmed in trans) for this variant and another variant classified as pathogenic by ClinGen MDEP (PM3_Strong; PMIDs: 14578306, 16026363, internal lab contributors). 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 0.847, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The Relative Activity Index (RAI) of this variant was found to be above the MDEP cutoff (0.5) for PS3_Moderate. While the p.Gly264Ser variant has been reported to cause protein misfolding, this is not considered to meet criteria for applying PS3_Supporting by the ClinGen MDEP (PMIDs: 22820548, 14578306, 16731834, https://doi.org/10.1159/000079009). In summary, c.790G>A 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, PS4, PP4_Moderate, PM3_Strong, PP2, PP3, PM2_Supporting. -

Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1865290:Hyperinsulinism due to glucokinase deficiency;C5393570:Permanent neonatal diabetes mellitus 1 Pathogenic:1

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PS4_Supporting+PP1_Moderate+PM3_Strong+PP4 -

Permanent neonatal diabetes mellitus Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;D;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;.;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	.;L;.;.;.
PhyloP100		6.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.2	.;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0040	.;D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;D
Polyphen		0.81	P;P;P;D;.
Vest4		0.57
MutPred		0.81		.;Loss of glycosylation at S263 (P = 0.0472);.;.;.;
MVP		0.96
MPC		1.8
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs193929373; hg19: chr7-44187322;