rs193922300

Variant names:

• chr7-44150982-G-A
• rs193922300
• NM_000162.5:c.457C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-44150982-G-A
• chr7-44150982-G-C

Variant summary

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

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:5 U:1
• 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.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.457C>T	p.Pro153Ser	missense_variant	Exon 4 of 10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.460C>T	p.Pro154Ser	missense_variant	Exon 4 of 10		NP_277042.1
GCK	NM_033508.3	c.454C>T	p.Pro152Ser	missense_variant	Exon 5 of 11		NP_277043.1
GCK	NM_001354800.1	c.457C>T	p.Pro153Ser	missense_variant	Exon 4 of 11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.457C>T	p.Pro153Ser	missense_variant	Exon 4 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Apr 08, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 18, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: 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. The variant was absent in 251460 control chromosomes. c.457C>T has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 2/Neonatal Diabetes Mellitus (Delvecchio_2017, Aloi_2017, Gaal_2021). These data indicate that the variant may 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: 28323911, 28726111, 34440516). ClinVar contains an entry for this variant (Variation ID: 36221). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1 Uncertain:1

Aug 29, 2024

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with autosomal dominant maturity-onset diabetes of the young (MODY). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 37101203, 38627865) Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. -

Aug 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 153 of the GCK protein (p.Pro153Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 28323911). ClinVar contains an entry for this variant (Variation ID: 36221). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Maturity onset diabetes mellitus in young Pathogenic:1

May 24, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 22, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

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;.;.;.
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;