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NM_000162.5(GCK):c.1302C>A (p.Cys434Ter) AND Monogenic diabetes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 25, 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:
RCV003313364.1

Allele description [Variation Report for NM_000162.5(GCK):c.1302C>A (p.Cys434Ter)]

NM_000162.5(GCK):c.1302C>A (p.Cys434Ter)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1302C>A (p.Cys434Ter)
Other names:
NM_001354803.2:c.336C>A
HGVS:
  • NC_000007.14:g.44145232G>T
  • NG_008847.2:g.57939C>A
  • NM_000162.5:c.1302C>AMANE SELECT
  • NM_001354800.1:c.1302C>A
  • NM_001354801.1:c.291C>A
  • NM_001354802.1:c.162C>A
  • NM_001354803.2:c.336C>A
  • NM_033507.3:c.1305C>A
  • NM_033508.3:c.1299C>A
  • NP_000153.1:p.Cys434Ter
  • NP_001341729.1:p.Cys434Ter
  • NP_001341730.1:p.Cys97Ter
  • NP_001341731.1:p.Cys54Ter
  • NP_001341732.1:p.Cys112Ter
  • NP_277042.1:p.Cys435Ter
  • NP_277043.1:p.Cys433Ter
  • LRG_1074t1:c.1302C>A
  • LRG_1074t2:c.1305C>A
  • LRG_1074:g.57939C>A
  • LRG_1074p1:p.Cys434Ter
  • LRG_1074p2:p.Cys435Ter
  • NC_000007.13:g.44184831G>T
Protein change:
C112*
Molecular consequence:
  • NM_000162.5:c.1302C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354800.1:c.1302C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354801.1:c.291C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354802.1:c.162C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354803.2:c.336C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_033507.3:c.1305C>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_033508.3:c.1299C>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
SCV004012139ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)		Pathogenic
(Jun 25, 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, SCV004012139.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1302C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 434 (p.(Cys434Ter)) of NM_000162.5. While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon 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 in gnomAD v2.1.1 (PM2_Supporting), and was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 28726111, PMID 19564454, internal lab contributor). One of these individuals had a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID 28726111). Additionally, this variant segregated with diabetes with 5 informative meioses in 2 families with MODY (PP1_Strong; PMID:28726111, internal lab contributor). In summary, the c.1302C>A variant 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, PP1_Strong, PP4_moderate, PS4_moderate, PM2_Supporting).

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

Last Updated: Jul 22, 2023