chr7-44151075-G-C

Position:

• chr7-44151075-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP1_Moderate PM5_Supporting PP2 PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.364C>G variant in the glucokinase gene, GCK, causes an amino acid change of leucine to valine at codon 122 (p.(Leu122Val)) 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 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 11508276, 32468610, internal lab contributors). Two of these individuals and one relative had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID:32468610, internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1; PMIDs: 32468610). Another missense variant, c.364C>T, p.Leu122Phe, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Taken together, this evidence supports the classification of c.364C>G 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): PP1_Moderate, PM5_Supporting, PM2_Supporting, PP2, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367402231/MONDO:0015967/086

• Frequency: Genomes: not found (cov: 32)
• Consequence: GCK ENST00000403799.8 missense, splice_region
• Scores: Splicing: ADA: 0.9497
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 5.88

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.364C>G	p.Leu122Val	missense_variant, splice_region_variant	4/10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.367C>G	p.Leu123Val	missense_variant, splice_region_variant	4/10		NP_277042.1
GCK	NM_033508.3	c.361C>G	p.Leu121Val	missense_variant, splice_region_variant	5/11		NP_277043.1
GCK	NM_001354800.1	c.364C>G	p.Leu122Val	missense_variant, splice_region_variant	4/11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.364C>G	p.Leu122Val	missense_variant, splice_region_variant	4/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2022	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 122 of the GCK protein (p.Leu122Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant maturity onset diabetes of the young (PMID: 11508276, 32468610). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 585919). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Leu122 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 15928245, 31905448), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 17, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 06, 2020	- -

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Mar 11, 2024

The c.364C>G variant in the glucokinase gene, GCK, causes an amino acid change of leucine to valine at codon 122 (p.(Leu122Val)) 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 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 11508276, 32468610, internal lab contributors). Two of these individuals and one relative had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 32468610, internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1; PMIDs: 32468610). Another missense variant, c.364C>T, p.Leu122Phe, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Taken together, this evidence supports the classification of c.364C>G 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): PP1_Moderate, PM5_Supporting, PM2_Supporting, PP2, PP3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.9	.;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.86
MutPred		0.94		.;Loss of catalytic residue at L122 (P = 0.0679);.;.;
MVP		0.97
MPC		2.2
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.89
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.76
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: rs1554335616; hg19: chr7-44190674;