NM_000162.5(GCK):c.370G>A (p.Asp124Asn) AND Monogenic diabetes

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 2, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001248968.8

Allele description [Variation Report for NM_000162.5(GCK):c.370G>A (p.Asp124Asn)]

NM_000162.5(GCK):c.370G>A (p.Asp124Asn)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.370G>A (p.Asp124Asn)

Other names:

NM_000162.5(GCK):c.370G>A

HGVS:

NC_000007.14:g.44151069C>T
NG_008847.2:g.52102G>A
NM_000162.3(GCK):c.370G>A
NM_000162.5:c.370G>AMANE SELECT
NM_001354800.1:c.370G>A
NM_033507.3:c.373G>A
NM_033508.3:c.367G>A
NP_000153.1:p.Asp124Asn
NP_001341729.1:p.Asp124Asn
NP_277042.1:p.Asp125Asn
NP_277043.1:p.Asp123Asn
LRG_1074t1:c.370G>A
LRG_1074t2:c.373G>A
LRG_1074:g.52102G>A
LRG_1074p1:p.Asp124Asn
LRG_1074p2:p.Asp125Asn
NC_000007.13:g.44190668C>T
NC_000007.13:g.44190668C>T
NM_000162.3(GCK):c.370G>A
NM_000162.3:c.370G>A
NM_000162.5:c.370G>A
p.ASP124ASN
p.Asp124Asn

Protein change:

D123N

Links:

dbSNP: rs759072800

NCBI 1000 Genomes Browser:

rs759072800

Molecular consequence:

NM_000162.5:c.370G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.370G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.373G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.367G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Monogenic diabetes
Identifiers:: MONDO: MONDO:0015967; MedGen: C3888631

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001422800	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 22, 2020)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 27059371, 24918535, 27106716, 20337973, 22773699, 25741868 Citation Link,
SCV003800669	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jan 25, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 20337973, 19790256, 33046911, 24578721, 34662886, 28842611, 36208030, 35176401, 32533152, 22773699, 24549415, 36400171, 30245511 Citation Link,
SCV004102852	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)	Pathogenic (Nov 2, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001422800

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 22, 2020)

germline

curation

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV003800669

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jan 25, 2023)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

Citation Link,

SCV004102852

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)

Pathogenic
(Nov 2, 2023)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Differential regulation of serum microRNA expression by HNF1β and HNF1α transcription factors.

Fendler W, Madzio J, Kozinski K, Patel K, Janikiewicz J, Szopa M, Tracz A, Borowiec M, Jarosz-Chobot P, Mysliwiec M, Szadkowska A, Hattersley AT, Ellard S, Malecki MT, Dobrzyn A, Mlynarski W.

Diabetologia. 2016 Jul;59(7):1463-1473. doi: 10.1007/s00125-016-3945-0. Epub 2016 Apr 8.

PubMed [citation]

PMID:: 27059371
PMCID:: PMC4901123

Genetic variability of GCKR alters lipid profiles in children with monogenic and autoimmune diabetes.

Tracz A, Madzio J, Gnys P, Malachowska B, Borowiec M, Wyka K, Jarosz-Chobot P, Mysliwiec M, Szadkowska A, Mlynarski W, Fendler W; PolPeDiab Study Group..

Exp Clin Endocrinol Diabetes. 2014 Oct;122(9):503-9. doi: 10.1055/s-0034-1375648. Epub 2014 Jun 11.

PubMed [citation]

PMID:: 24918535

See all PubMed Citations (17)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422800.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

The p.Asp124Asn variant in GCK has been reported in at least 6 individuals (including 1 Polish, 1 Czech, 1 German, and 2 Caucasian individuals) with Monogenic Diabetes (PMID: 27106716, 22773699, 24918535, 20337973; DOI: 10.2337/db18-1509-P), and has been identified in 0.002893% (1/34564) of Latino chromosomes and 0.0008805% (1/113574) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs759072800). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 211073). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in GCK in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP2, PP3 (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003800669.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

Variant summary: GCK c.370G>A (p.Asp124Asn) 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 allele was found at a frequency of 8e-06 in 251174 control chromosomes (gnomAD). c.370G>A has been reported in the literature in several individuals affected with Monogenic Diabetes (e.g. Osbak_2009, Pruhova_2010, Fendler_2014, Caswell_2020, Bonneford_2020, Bodis_2022, Gjesing_2022), including a family with multiple affected members (Bodis_2022), however the variant was also found in healthy control(s) (Bonneford_2020). In a recent large study evaluating UK Biobank data, the variant was found in 3/14622 diabetes cases and 10/185509 controls without diagnosis of diabetes (Billings_2022). These data indicate that the variant is likely to be associated with disease, but might also suggest a reduced penetrance. At least one publication also reported in vivo functional analysis (euglycemic-hyperinsulinemic clamp) performed in two carriers heterozygous for the D124N variant, and found impairments of insulin-secretion, with beta-cell function about 50% of the controls (Bodis_2022). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and reported the variant with conflicting assessments, i.e. as VUS (n=2), likely pathogenic (n=1) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004102852.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.370G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 124 (p.(Asp124Asn)) 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 0.817, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to one copy in the European non-Finnish subpopulation and one copy in the Latino/Admixed American subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 14 unrelated individuals with hyperglycemia (PS4; PMIDs: 20337973, 22773699, internal lab contributors). This variant was identified in a at least three individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with seven informative meioses in five families (PP1_Strong; internal lab contributors). In summary, c.379G>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): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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