rs193922300

Positions:

• chr7-44150982-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5_Supporting PP2 PP3 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.457C>T variant in the glucokinase gene, GCK, causes an amino acid change of proline to serine at codon 153 (p.(Pro153Ser)) 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 0.973, 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 five unrelated individuals with hyperglycemia (PS4_Moderate; PMID:28726111, internal lab contributors). Another missense variant, c.458C>A p.Pro153His, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to FBG above the guideline range (internal lab contributors). In summary, c.457C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM5_Supporting, PS4_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213788/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:2
• Conservation: PhyloP100: 9.92

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 Likely_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.457C>T	p.Pro153Ser	missense_variant	4/10	ENST00000403799.8
GCK	NM_033507.3	c.460C>T	p.Pro154Ser	missense_variant	4/10
GCK	NM_033508.3	c.454C>T	p.Pro152Ser	missense_variant	5/11
GCK	NM_001354800.1	c.457C>T	p.Pro153Ser	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.457C>T	p.Pro153Ser	missense_variant	4/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Apr 08, 2024

A GCK c.457C>T (p.Pro153Ser) variant was identified. This variant has been reported in several individuals with maturity onset diabetes of the young and is reported to segregate with disease in at least two families (Delvecchio M et al., PMID: 28323911; Aloi C et al., PMID: 28726111; Ga√°l Z et al. PMID: 34440516). The GCK c.457C>T (p.Pro153Ser) variant has been reported in the ClinVar database as a germline variant of uncertain clinical significance by two submitters and a likely pathogenic variant by one submitter (ClinVar Variation ID: 36221). This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. It resides within a region, the glucose binding site, amino acids 151-153, of the GCK gene that is defined as a critical functional domain (Petit P et al., PMID: 22101819). Another variant in the same codon, GCK c.459T>G (p.Pro153Pro) has been reported in one individual with maturity-onset diabetes of the young (MODY) and is considered pathogenic based on it's impact on splicing (Costantini, S et al., PMID: 21288587; ClinVar Variation ID: 972810). Computational predictors suggest that this variant is damaging, evidence that correlates with impact on GCK function. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868) and based on ClinGen Monogenic Diabetes expert panel, the GCK c.457C>T (p.Pro153Ser) variant is classified as likely pathogenic. -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2022

The p.P153S variant (also known as c.457C>T), located in coding exon 4 of the GCK gene, results from a C to T substitution at nucleotide position 457. The proline at codon 153 is replaced by serine, an amino acid with similar properties. This variant was detected in one individual from a cohort of 3781 consecutive patients diagnosed with diabetes or impaired fasting glucose (<18 years) with negative type 1 diabetes antibodies (Delvecchio M et al. J. Clin. Endocrinol. Metab., 2017 06;102:1826-1834) and was later reported to segregate with disease in an Italian family in which the proband was diagnosed with impaired fasting glucose at 5 years of age and was described as having normal glucose tolerance, HbA1C of 6.5%, normal BMI and mother with gestational diabetes (Aloi C et al. Acta Diabetol, 2017 Oct;54:913-923). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function and is more disruptive than nearby pathogenic variants (Petit P et al. Acta Crystallogr. D Biol. Crystallogr., 2011 Nov;67:929-35). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 22, 2024

The c.457C>T variant in the glucokinase gene, GCK, causes an amino acid change of proline to serine at codon 153 (p.(Pro153Ser)) 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 0.973, 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 five unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 28726111, internal lab contributors). Another missense variant, c.458C>A p.Pro153His, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to FBG above the guideline range (internal lab contributors). In summary, c.457C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM5_Supporting, PS4_Moderate, PM2_Supporting. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 04, 2019

Variant summary: The variant, GCK c.457C>T (p.Pro153Ser) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function consistent with an ExAC z score of 4.39 indicative of a gene relatively intolerant to benign missense variation (ACMG PP3, PP2). The variant was absent in 246268 control chromosomes (gnomAD) (ACMG PM2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.457C>T has been reported in the literature in an individual affected with Maturity Onset Diabetes of the Young 2/Neonatal Diabetes Mellitus (Aloi_2017). However, this data does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. As summarized above, at-least one new report indicating its presence in an individual diagnosed with MODY or a related diabetic phenotype have emerged since its original classification. Based on the evidence outlined above, until unequivocal co-segregation with disease in additional families/individuals with MODY2/NDM and functional studies corroborating the evidence described above is obtained, the variant was conservatively classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;.;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.5	.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.0	.;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.97
MutPred		0.95		.;Gain of catalytic residue at P153 (P = 0.0195);.;.;.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.93
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: rs193922300; hg19: chr7-44190581;