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NM_000162.5(GCK):c.1020-1G>A AND Monogenic diabetes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 31, 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:
RCV003993666.1

Allele description [Variation Report for NM_000162.5(GCK):c.1020-1G>A]

NM_000162.5(GCK):c.1020-1G>A

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1020-1G>A
HGVS:
  • NC_000007.14:g.44145731C>T
  • NG_008847.2:g.57440G>A
  • NM_000162.5:c.1020-1G>AMANE SELECT
  • NM_001354800.1:c.1020-1G>A
  • NM_001354801.1:c.9-1G>A
  • NM_001354802.1:c.-121-1G>A
  • NM_001354803.2:c.54-1G>A
  • NM_033507.3:c.1023-1G>A
  • NM_033508.3:c.1017-1G>A
  • LRG_1074t1:c.1020-1G>A
  • LRG_1074t2:c.1023-1G>A
  • LRG_1074:g.57440G>A
  • NC_000007.13:g.44185330C>T
  • NM_000162.3:c.1020-1G>A
Links:
dbSNP: rs193922258
NCBI 1000 Genomes Browser:
rs193922258
Molecular consequence:
  • NM_000162.5:c.1020-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354800.1:c.1020-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354801.1:c.9-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354802.1:c.-121-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354803.2:c.54-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_033507.3:c.1023-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_033508.3:c.1017-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

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

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004812206ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)		Pathogenic
(Mar 31, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004812206.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1020-1G>A variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 8 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 9 of 10, resulting in deletion of >10% of a protein encoded by 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 3 apparently unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). Two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies or 2 hour OGTT increment < 3 mmol/L)(PP4_Moderate, internal lab contributors). This variant segregated with hyperglycemia with 2 informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.1020-1G>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, approved 8/11/2023): PVS1, PP4_Moderate, PM2_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 7, 2024