7-44145521-C-T

Position:

• chr7-44145521-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM5 PP4_Moderate PP2 PP3 PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1229G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to aspartate at codon 410 (p.(Gly410Asp)) 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 ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.991, 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 segregated with hyperglycemia, with 2 informative meioses in 2 families (PP1; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Another missense variant, c.1228G>A p.Gly410Ser, has been interpreted as pathogenic by the ClinGen MDEP, and p.Gly410Asp has a greater Grantham distance (PM5). In summary, c.1229G>A 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, PP1, PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367398309/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCK ENST00000403799.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 7.85

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 10 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.
• 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.1229G>A	p.Gly410Asp	missense_variant	9/10	ENST00000403799.8	NP_000153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.1229G>A	p.Gly410Asp	missense_variant	9/10	1	NM_000162.5	ENSP00000384247	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456610 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 30, 2019	DNA sequence analysis of the GCK gene demonstrated a sequence change, c.1229G>A, in exon 9 that results in an amino acid change, p.Gly410Asp. The p.Gly410Asp change affects a highly conserved amino acid residue located in the alpha 14 helix domain of the GCK protein that is known to be functional. The p.Gly410Asp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This is a novel sequence change that is not present in the population databases (ExAC and gnomAD). This particular amino acid change has been identified in a patient with clinical diagnosis of maturity onset diabetes of the young (MODY) (PMID: 31063852). Additionally, PMID: 28726111 identified a different missense variant, c.1229G>T(p.Gly410Val), affecting the same amino acid residue in a 4 year old patient with a clinical diagnosis of MODY. Furthermore, the p.Gly410Asp amino acid change occurs in a region of the GCK gene where other missense sequence changes have been described in patients with GCK-MODY. These collective evidences indicate that this sequence change is the likely cause of this phenotype, however functional studies have not been performed to prove this conclusively. -
Uncertain significance, flagged submission	clinical testing	Athena Diagnostics	Dec 28, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2024	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31063852) -

Monogenic diabetes Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Jun 22, 2024	The c.1229G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to aspartate at codon 410 (p.(Gly410Asp)) 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 ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.991, 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 segregated with hyperglycemia, with 2 informative meioses in 2 families (PP1; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Another missense variant, c.1228G>A p.Gly410Ser, has been interpreted as pathogenic by the ClinGen MDEP, and p.Gly410Asp has a greater Grantham distance (PM5). In summary, c.1229G>A 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, PP1, PP4_moderate. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 22, 2024	Variant summary: GCK c.1229G>A (p.Gly410Asp) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1229G>A has been reported in the literature in individuals affected with Monogenic Diabetes (examples: Sanyoura_2019, Mirshahi_2022). 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. Other variants affecting this residue have been classified Pathogenic in ClinVar (CV ID:3233996, 3233995, 1472875). This suggests that the residue may play a critical role in protein function. The following publications have been ascertained in the context of this evaluation (PMID: 36257325, 31063852). ClinVar contains an entry for this variant (Variation ID: 447386). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

GCK-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2024

The GCK c.1229G>A variant is predicted to result in the amino acid substitution p.Gly410Asp. This variant has been reported in an individual with MODY (Sanyoura et al. 2019. PubMed ID: 31063852). Alternate nucleotide changes affecting the same amino acid (p.Gly410Val, p.Gly410Ser, p.Gly410Arg), have been reported in individuals with MODY and diabetes (Aloi et al. 2017. PubMed ID: 28726111; Park et al. 2019. PubMed ID: 30977832; described as 7:44145522:C:G, Table S7, Jurgens et al. 2022. PubMed ID: 35177841). The p.Gly410 residue is located in the critical hexokinase C-terminal domain and a functional study of the alternate variant p.Gly410Val showed the mutation impacted the ATP binding process and glucose phosphorylation which had an effect on the enzyme stability (Aloi et al. 2017. PubMed ID: 28726111). This variant has not been reported in a large population database, indicating this variant is rare. Taken together, c.1229G>A p.Gly410Asp is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;D;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.0	.;.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.0	.;D;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D
Vest4		0.98
MutPred		0.98		.;.;Loss of MoRF binding (P = 0.074);.;.;.;
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
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: rs1554334546; hg19: chr7-44185120;