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NM_000162.5(GCK):c.1254-1G>T AND Monogenic diabetes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 26, 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:
RCV003313371.1

Allele description [Variation Report for NM_000162.5(GCK):c.1254-1G>T]

NM_000162.5(GCK):c.1254-1G>T

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1254-1G>T
Other names:
NM_001354803.2:c.288-1G>T
HGVS:
  • NC_000007.14:g.44145281C>A
  • NG_008847.2:g.57890G>T
  • NM_000162.5:c.1254-1G>TMANE SELECT
  • NM_001354800.1:c.1254-1G>T
  • NM_001354801.1:c.243-1G>T
  • NM_001354802.1:c.114-1G>T
  • NM_001354803.2:c.288-1G>T
  • NM_033507.3:c.1257-1G>T
  • NM_033508.3:c.1251-1G>T
  • LRG_1074t1:c.1254-1G>T
  • LRG_1074t2:c.1257-1G>T
  • LRG_1074:g.57890G>T
  • NC_000007.13:g.44184880C>A
Molecular consequence:
  • NM_000162.5:c.1254-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354800.1:c.1254-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354801.1:c.243-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354802.1:c.114-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354803.2:c.288-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_033507.3:c.1257-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_033508.3:c.1251-1G>T - 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
SCV004012146ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)		Pathogenic
(Jun 26, 2023) 		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, SCV004012146.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1254-1G>T variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 9 of NM_000162.5. While this variant is predicted to cause skipping of exon 10 and to escape nonsense mediated decay, it is in a functionally important region of a gene where 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 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: 24735133). The c.1254-1G>C variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.1254-1G>T has a similar predicted impact by Splice AI (0.95 and 0.95) (PS1_Supporting). In summary, c.1254-1G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting, PP4, PS1_Supporting.

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

Last Updated: Jul 22, 2023