7-44145614-G-T

Position:

• chr7-44145614-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3 PS4_Moderate PP2 PP3 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1136C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 379 (p.(Ala379Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, 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 non-autoimmune/insulin-deficient diabetes (PS4_Moderate; PMID 30592380, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID:30592389) (PP4; internal lab contributors). This variant has been detected in one individual with neonatal diabetes. This individual was compound heterozygous for the variant and a pathogenic variant and was confirmed in trans by parental/family testing (PM3; PMID 30592380). Functional studies demonstrated the p.Ala379Glu protein has RAI<0.5; however, the wild-type kinetic parameters didn’t pass the quality control, and the PS3 cannot be applied (PMID:30592380). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4, PM3, PS4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213717/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: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 8.02

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 8 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.
• PM3: 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.1136C>A	p.Ala379Glu	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.1136C>A	p.Ala379Glu	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: 1454700 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723700

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: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 30, 2019

Variant summary: GCK c.1136C>A (p.Ala379Glu) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function consistent with an ExAC z score of 4.39 indicative of a gene relatively intolerant to benign missense variation (ACMG PP3, PP2). The variant was absent in 231278 control chromosomes (gnomAD)(ACMG PM2). c.1136C>A has been reported in the literature in individuals affected with Maturity Onset Diabetes of the Young 2/Neonatal Diabetes Mellitus (Wang_2018, Wildhardt_2010, Osbak_2009). These data indicate that the variant is likely to be associated with disease (ACMG PS4 and PP1-supporting). Experimental evidence evaluating an impact on protein function demonstrated the variant to be kinetically inactivating, with decreased rate of catalysis and decreased affinity for glucose and ATP and thermal instability as demonstrated by decreased enzyme activity at increased incubation temperature; the authors of the study concluded that the changes in enzyme kinetics and thermostability may be the pathogenic mechanisms by which the variant causes hyperglycemia (ACMG PS3). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. As summarized above, at-least two new reports indicating its presence in individuals diagnosed with MODY or a related diabetic phenotype supported by functional evidence have emerged since its original classification. Based on the evidence outlined above, until unequivocal co-segregation with disease in additional families/individuals with MODY2/NDM and additional functional studies corroborating the evidence described above is obtained, the variant was conservatively classified as likely pathogenic. -

Monogenic diabetes Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Jul 17, 2023

The c.1136C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 379 (p.(Ala379Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, 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 non-autoimmune/insulin-deficient diabetes (PS4_Moderate; PMID 30592380, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 30592389) (PP4; internal lab contributors). This variant has been detected in one individual with neonatal diabetes. This individual was compound heterozygous for the variant and a pathogenic variant and was confirmed in trans by parental/family testing (PM3; PMID 30592380). Functional studies demonstrated the p.Ala379Glu protein has RAI<0.5; however, the wild-type kinetic parameters didn’t pass the quality control, and the PS3 cannot be applied (PMID: 30592380). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4, PM3, PS4_Moderate. -

Maturity onset diabetes mellitus in young Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2020

The p.A379E variant (also known as c.1136C>A), located in coding exon 9 of the GCK gene, results from a C to A substitution at nucleotide position 1136. The alanine at codon 379 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration was confirmed in trans with a second disease-causing allele in a patient with neonatal diabetes mellitus (Wang Z et al. J Diabetes Investig, 2019 Jul;10:963-971). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Functional analysis revealed that A379E results in decreased enzyme activity as compared to wild-type (Wang Z et al. J Diabetes Investig, 2019 Jul;10:963-971). Based on internal structural analysis, A379E is more destabilizing to the structure of the hexokinase domain of GCK than several pathogenic variants within 20 Å and in the same domain (Petit P et al. Acta Crystallogr. D Biol. Crystallogr., 2011 Nov;67:929-35; Estalella I et al. J. Hum. Genet., 2008 Mar;53:460-466; Miller SP et al. Diabetes, 1999 Aug;48:1645-51; Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26). Another alteration at the same codon, p.A379V (c.1136C>T), has been described (Estalella I et al. J. Hum. Genet., 2008 Mar;53:460-466; Weinert LS et al. Diabetes Res. Clin. Pract., 2014 Nov;106:e44-8). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 16, 2021

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 heterozygous individual with clinical features of maturity-onset diabetes of the young, type 2 (MODY2) and in one compound heterozygous individual with neonatal diabetes mellitus, within the same family (PMID: 30592380). This variant appears to occur de novo in one individual with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant results in reduced enzyme activity compared to the wild type (PMID: 30592380). Computational tools predict that this variant is damaging. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	.;D;D;.;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.0	.;.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-4.8	.;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.99	D;.;D;D;D;D
Vest4		0.84
MutPred		0.98		.;.;Gain of disorder (P = 0.0373);.;.;.;
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		5.2
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: rs193922265; hg19: chr7-44185213;