rs1064793998

Positions:

• chr7-44153325-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS4_Moderate PP1_Strong PS3_Supporting PP4_Moderate PP2 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.184G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 62 (p.(Val62Met)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.972, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While p.Val62Met did not have reduction in enzyme activity or stability, its activity was unresponsive to GKRP (PS3_Supporting; PMID 15677479). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:15677479, PMID:28726111, ClinVar ID: 419624, internal lab contributors). At least two of these individuals had a clinical history highly specific for for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:15677479). This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; PMID:15677479). In summary, c.184G>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, PP4_moderate, PS4_moderate, PP2, PP3, PM2_Supporting, PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16618472/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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.
• 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.184G>A	p.Val62Met	missense_variant	2/10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.187G>A	p.Val63Met	missense_variant	2/10		NP_277042.1
GCK	NM_033508.3	c.181G>A	p.Val61Met	missense_variant	3/11		NP_277043.1
GCK	NM_001354800.1	c.184G>A	p.Val62Met	missense_variant	2/11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.184G>A	p.Val62Met	missense_variant	2/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461804 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 21, 2021	Variant summary: GCK c.184G>A (p.Val62Met) results in a conservative amino acid change located in the Hexokinase, N-terminal of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251306 control chromosomes. c.184G>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 2/Neonatal Diabetes Mellitus and has been shown to segregate with disease in several families (Gloyn_2005, Aloi_2017). These data indicate that the variant is very likely to be associated with disease. The variant has been reported in functional studies to result in lowered catalytic activity/impaired enzyme activity, decreased thermal stability and/or reduced aglucose affinity (Gloyn_2005, Arden_2007, Ralph_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Translational Genomics Laboratory, University of Maryland School of Medicine	Mar 12, 2018	The c.184G>A variant in codon 62 (exon 3 of the RefSeqGene and of NM_000162.3) of the glucokinase gene, GCK, results in the substitution of Valine to Methionine. Missense mutations in GCK, including ones in this exon, have been reported in patients with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (19790256). The c.184G>A variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, the c.184G>A variant was previously shown to segregate with elevated fasting plasma glucose in three families (15677479, 27271189), A different amino acid substitution at this residue, p.Val62Ala, was shown to segregate with diabetes and impaired glucose tolerance in multiple individuals across four generations in a Norwegian family (9736233, 18399931). Additionally, multiple lines of computational evidence (MutationTaster, FATHMM, MetaSVM, MetalR, Provean, LRT, SIFT, Polyphen, GERP, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. Indeed, functional studies have demonstrated impaired enzyme activity of both the p.Val62Met and p.Val62Ala mutant proteins (15677479, 16731834, 17389332, 19187021). ACMG criteria = PP1strong, PS4mod, PS3, PM2, PP3 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 17, 2023	This variant has been identified in at least one individual with MODY and appears to segregate with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15677479, 16938872, 17389332, 19187021) -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2023	Published functional studies do not consistently show lowered catalytic activity in standard assays but provide some evidence for decreased thermal stability, or reduced interaction with regulatory proteins (PMID: 17389332, 19187021, 21831042); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21104275, 18322640, 16731834, 17389332, 19187021, 21831042, 19790256, 28726111, 15677479, 37101203, 27271189, 18481947, 18399931, 36257325, 17186219, 16938872, 36880032) -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Aug 25, 2023

The c.184G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 62 (p.(Val62Met)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.972, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While p.Val62Met did not have reduction in enzyme activity or stability, its activity was unresponsive to GKRP (PS3_Supporting; PMID 15677479). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:15677479, PMID: 28726111, ClinVar ID: 419624, internal lab contributors). At least two of these individuals had a clinical history highly specific for for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:15677479). This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; PMID: 15677479). In summary, c.184G>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, PP4_moderate, PS4_moderate, PP2, PP3, PM2_Supporting, PS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;.;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.8	.;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.95
MutPred		0.96		.;Gain of disorder (P = 0.0551);.;.;Gain of disorder (P = 0.0551);
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.90
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

LitVar

Other links and lift over

dbSNP: rs1064793998; hg19: chr7-44192924;