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NM_000162.5(GCK):c.324C>A (p.Tyr108Ter) AND Monogenic diabetes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 15, 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:
RCV003481520.1

Allele description [Variation Report for NM_000162.5(GCK):c.324C>A (p.Tyr108Ter)]

NM_000162.5(GCK):c.324C>A (p.Tyr108Ter)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.324C>A (p.Tyr108Ter)
Other names:
NM_033508.3:c.321C>A
HGVS:
  • NC_000007.14:g.44152310G>T
  • NG_008847.2:g.50861C>A
  • NM_000162.5:c.324C>AMANE SELECT
  • NM_001354800.1:c.324C>A
  • NM_033507.3:c.327C>A
  • NM_033508.3:c.321C>A
  • NP_000153.1:p.Tyr108Ter
  • NP_001341729.1:p.Tyr108Ter
  • NP_277042.1:p.Tyr109Ter
  • NP_277043.1:p.Tyr107Ter
  • LRG_1074t1:c.324C>A
  • LRG_1074t2:c.327C>A
  • LRG_1074:g.50861C>A
  • LRG_1074p1:p.Tyr108Ter
  • LRG_1074p2:p.Tyr109Ter
  • NC_000007.13:g.44191909G>T
Protein change:
Y107*
Molecular consequence:
  • NM_000162.5:c.324C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354800.1:c.324C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_033507.3:c.327C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_033508.3:c.321C>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV004223879ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)		Pathogenic
(Dec 15, 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, SCV004223879.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.324C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 108 (p.(Tyr108Ter)) of NM_000162.5. This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; 19790256). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 14517956, internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.324C>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): PVS1, PP4, PM2_Supporting.

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

Last Updated: Jan 26, 2024