7-44147825-A-G

Position:

• chr7-44147825-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM5_Supporting PP2 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.688T>C variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to arginine at codon 230 (p.(Cys230Arg)) 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 resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.85, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in three unrelated individuals with hyperglycemia; however, this does not meet the threshold set by the ClinGen MDEP for the application of PS4 (internal lab contributors). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, the fasting blood sugar was slightly below the threshold for PP4 (5.5 mmol/L) (internal lab contributors). Another missense variant, c.689G>A p.Cys230Tyr, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Cys230Arg (PM5_Supporting). In summary, c.688T>C 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): PM1, PP2, PP3, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA247034/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCK ENST00000403799.8 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:4 O:1
• Conservation: PhyloP100: 5.21

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]

LOC105375258 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: 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/exons	MANE	Protein	UniProt
GCK	NM_000162.5	c.688T>C	p.Cys230Arg	missense_variant	7/10	ENST00000403799.8	NP_000153.1
LOC105375258	XR_927223.3	n.98+77A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.688T>C	p.Cys230Arg	missense_variant	7/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2024	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18397317, 22101819, 15016359) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 230 of the GCK protein (p.Cys230Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GCK-related conditions. ClinVar contains an entry for this variant (Variation ID: 198397). 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. 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	Athena Diagnostics	Aug 13, 2018	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Mar 22, 2022

Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:25306193,28323911). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85>=0.6, 3CNET: 0.994>=0.75). A missense variant is a common mechanism associated with MODY, type II. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Dec 02, 2023

The c.688T>C variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to arginine at codon 230 (p.(Cys230Arg)) 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 resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.85, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in three unrelated individuals with hyperglycemia; however, this does not meet the threshold set by the ClinGen MDEP for the application of PS4 (internal lab contributors). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, the fasting blood sugar was slightly below the threshold for PP4 (5.5 mmol/L) (internal lab contributors). Another missense variant, c.689G>A p.Cys230Tyr, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Cys230Arg (PM5_Supporting). In summary, c.688T>C 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): PM1, PP2, PP3, PM2_Supporting, PM5_Supporting. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 13, 2022

Variant summary: GCK c.688T>C (p.Cys230Arg) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Other amino acid changes located at the same codon (p.Cys230Gly and p.Cys230Tyr) and in vicinity have been reported in association with Monogenic Diabetes suggesting the functional relevance of this residue to overall Glucokinase protein function. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250196 control chromosomes. To our knowledge, no occurrence of c.688T>C in individuals affected with Monogenic Diabetes and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (LP, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Maturity onset diabetes mellitus in young Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs794727839 in MODY, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.65	.;D;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.59	T;T;.;T;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	.;N;N;N;N
REVEL	Pathogenic	0.85
Sift	Uncertain	0.021	.;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		0.86	P;P;P;D;.
Vest4		0.91
MutPred		0.82		.;Gain of sheet (P = 0.0827);.;.;.;
MVP		0.99
MPC		2.6
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.98
gMVP		1.0

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: rs794727839; hg19: chr7-44187424;