7-44150990-A-T

Position:

• chr7-44150990-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP1_Moderate PP4_Moderate PP2 PP3 PS3_Moderate PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The c.449T>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to tyrosine at codon 150 (p.(Phe150Tyr)) 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 0.962, 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 10 unrelated individuals with hyperglycemia (PS4; PMIDs: 25306193, 19564454, 32086287, 30663027, 28726111, 22761713, internal lab contributors). One of these individuals had 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; PMID:28726111). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.014, which is below the MDEP cutoff (<0.5) (PS3_Moderate, PMID:22761713). In summary, c.449T>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): PS4, PP1_Moderate, PP4_Moderate, PS3_Moderate, PP2, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA231135/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 9.25

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 13 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCK	NM_000162.5	c.449T>A	p.Phe150Tyr	missense_variant	4/10	ENST00000403799.8
GCK	NM_033507.3	c.452T>A	p.Phe151Tyr	missense_variant	4/10
GCK	NM_033508.3	c.446T>A	p.Phe149Tyr	missense_variant	5/11
GCK	NM_001354800.1	c.449T>A	p.Phe150Tyr	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCK	ENST00000403799.8	c.449T>A	p.Phe150Tyr	missense_variant	4/10	1	NM_000162.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Jan 06, 2024	The c.449T>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to tyrosine at codon 150 (p.(Phe150Tyr)) 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 0.962, 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 10 unrelated individuals with hyperglycemia (PS4; PMIDs: 25306193, 19564454, 32086287, 30663027, 28726111, 22761713, internal lab contributors). One of these individuals had 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; PMID: 28726111). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.014, which is below the MDEP cutoff (<0.5) (PS3_Moderate, PMID: 22761713). In summary, c.449T>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): PS4, PP1_Moderate, PP4_Moderate, PS3_Moderate, PP2, PP3, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 23, 2023	Variant summary: GCK c.449T>A (p.Phe150Tyr) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) 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 251462 control chromosomes. c.449T>A has been reported in the literature in settings of individuals affected with incidental hyperglycemia, MODY, gestational/monogenic diabetes and laboratory testing cohorts (example, Lorini_2009, Capuano_2012, Alkorta-Aranburu_2014, Aloi_2017, Zubkova_2019, Stankute_2020, Ivanoshchuk_2021). Of these, only the subset of individuals/cohorts reporting diagnostic findings supportive of MODY/monogenic diabetes were captured in this ascertainment (example, Aloi_2017, Stankute_2020, Ivanoshchuk_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Capuano_2012). The most pronounced variant effect results in <10% of normal GCK activity in-vitro. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 24, 2023	This sequence change replaces phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 150 of the GCK protein (p.Phe150Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant GCK-related conditions (PMID: 19564454). ClinVar contains an entry for this variant (Variation ID: 129142). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCK protein function. Experimental studies have shown that this missense change affects GCK function (PMID: 22761713). This variant disrupts the p.Phe150 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 12627330), which suggests that this may be a clinically significant amino acid residue. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 21, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.8	.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.0	.;D;D;D;D
REVEL	Pathogenic	0.96
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		0.92
MutPred		0.98		.;Gain of phosphorylation at F150 (P = 0.1295);.;.;.;
MVP		0.96
MPC		2.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.93
gMVP		0.98

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: rs193922297; hg19: chr7-44190589;