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NM_000162.5(GCK):c.1261G>T (p.Glu421Ter) AND Maturity-onset diabetes of the young type 2

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:
RCV003313366.1

Allele description [Variation Report for NM_000162.5(GCK):c.1261G>T (p.Glu421Ter)]

NM_000162.5(GCK):c.1261G>T (p.Glu421Ter)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1261G>T (p.Glu421Ter)
Other names:
NM_001354803.2:c.295G>T
HGVS:
  • NC_000007.14:g.44145273C>A
  • NG_008847.2:g.57898G>T
  • NM_000162.5:c.1261G>TMANE SELECT
  • NM_001354800.1:c.1261G>T
  • NM_001354801.1:c.250G>T
  • NM_001354802.1:c.121G>T
  • NM_001354803.2:c.295G>T
  • NM_033507.3:c.1264G>T
  • NM_033508.3:c.1258G>T
  • NP_000153.1:p.Glu421Ter
  • NP_001341729.1:p.Glu421Ter
  • NP_001341730.1:p.Glu84Ter
  • NP_001341731.1:p.Glu41Ter
  • NP_001341732.1:p.Glu99Ter
  • NP_277042.1:p.Glu422Ter
  • NP_277043.1:p.Glu420Ter
  • LRG_1074t1:c.1261G>T
  • LRG_1074t2:c.1264G>T
  • LRG_1074:g.57898G>T
  • LRG_1074p1:p.Glu421Ter
  • LRG_1074p2:p.Glu422Ter
  • NC_000007.13:g.44184872C>A
Protein change:
E41*
Molecular consequence:
  • NM_000162.5:c.1261G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354800.1:c.1261G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354801.1:c.250G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354802.1:c.121G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354803.2:c.295G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_033507.3:c.1264G>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_033508.3:c.1258G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Maturity-onset diabetes of the young type 2
Synonyms:
MODY type 2; Diabetes mellitus MODY type 2; MODY glucokinase-related; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007453; MedGen: C0342277; Orphanet: 552; OMIM: 125851

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004012141ClinGen 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, SCV004012141.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1261G>T variant in the glucokinase gene, GCK, results in a premature termination at codon 421 (p.(Glu421Ter)) 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). This variant is absent in 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% and fasting glucose between 5.5-8 mmol/L) (PP4; internal lab contributors). In summary, c.1261G>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.

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

Last Updated: Jul 29, 2023