NM_000162.5(GCK):c.680-2A>G AND Monogenic diabetes

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 28, 2024
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:: RCV002298750.3

Allele description [Variation Report for NM_000162.5(GCK):c.680-2A>G]

NM_000162.5(GCK):c.680-2A>G

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.680-2A>G

HGVS:

NC_000007.14:g.44147835T>C
NG_008847.2:g.55336A>G
NM_000162.5:c.680-2A>GMANE SELECT
NM_001354800.1:c.680-2A>G
NM_033507.3:c.683-2A>G
NM_033508.3:c.677-2A>G
LRG_1074t1:c.680-2A>G
LRG_1074t2:c.683-2A>G
LRG_1074:g.55336A>G
NC_000007.13:g.44187434T>C
NM_000162.3:c.680-2A>G

Links:

dbSNP: rs1562715657

NCBI 1000 Genomes Browser:

rs1562715657

Molecular consequence:

NM_000162.5:c.680-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354800.1:c.680-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_033507.3:c.683-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_033508.3:c.677-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV002598565	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 23, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19790256, 31704690, 36257325 Citation Link,
SCV004697920	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)	Pathogenic (Feb 28, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002598565

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 23, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004697920

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)

Pathogenic
(Feb 28, 2024)

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

Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia.

Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S, Gloyn AL.

Hum Mutat. 2009 Nov;30(11):1512-26. doi: 10.1002/humu.21110. Review.

PubMed [citation]

PMID:: 19790256

Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Should Lead to Testing for MODY: Lessons From a 5-Year Pediatric Swedish National Cohort Study.

Carlsson A, Shepherd M, Ellard S, Weedon M, Lernmark Å, Forsander G, Colclough K, Brahimi Q, Valtonen-Andre C, Ivarsson SA, Elding Larsson H, Samuelsson U, Örtqvist E, Groop L, Ludvigsson J, Marcus C, Hattersley AT.

Diabetes Care. 2020 Jan;43(1):82-89. doi: 10.2337/dc19-0747. Epub 2019 Nov 8.

PubMed [citation]

PMID:: 31704690
PMCID:: PMC6925576

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002598565.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: GCK c.680-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the 3' canonical acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249710 control chromosomes. c.680-2A>G has been reported in the literature in multiple individuals affected with Monogenic Diabetes (examples: Osbak_2009, Carlsson_2020, Mirshahi_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31704690, 36257325, 19790256). ClinVar contains an entry for this variant (Variation ID: 585924). Based on the evidence outlined above, the variant was classified as 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, SCV004697920.1

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

Description

The c.680-2A>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 6 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 7 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4: PMIDs: 19790256, 31704690, 36257325, 34362814, ClinVar ID:585924). At least 2 of these individuals had a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 31704690). In summary, c.680-2A>G 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, approved 8/11/2023): PVS1, PS4, 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 8, 2024

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