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NM_000162.5(GCK):c.1280_1283dup (p.Arg429fs) AND Maturity-onset diabetes of the young type 2

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 3, 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:
RCV003399057.1

Allele description [Variation Report for NM_000162.5(GCK):c.1280_1283dup (p.Arg429fs)]

NM_000162.5(GCK):c.1280_1283dup (p.Arg429fs)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1280_1283dup (p.Arg429fs)
Other names:
NM_000162.5(GCK):c.1280_1283dup; p.Arg429fs
HGVS:
  • NC_000007.14:g.44145254_44145257dup
  • NG_008847.2:g.57917_57920dup
  • NM_000162.5:c.1280_1283dupMANE SELECT
  • NM_001354800.1:c.1280_1283dup
  • NM_001354801.1:c.269_272dup
  • NM_001354802.1:c.140_143dup
  • NM_001354803.2:c.314_317dup
  • NM_033507.3:c.1283_1286dup
  • NM_033508.3:c.1277_1280dup
  • NP_000153.1:p.Arg429fs
  • NP_001341729.1:p.Arg429fs
  • NP_001341730.1:p.Arg92fs
  • NP_001341731.1:p.Arg49fs
  • NP_001341732.1:p.Arg107fs
  • NP_277042.1:p.Arg430fs
  • NP_277043.1:p.Arg428fs
  • LRG_1074t1:c.1280_1283dup
  • LRG_1074t2:c.1283_1286dup
  • LRG_1074:g.57917_57920dup
  • LRG_1074p1:p.Arg429fs
  • LRG_1074p2:p.Arg430fs
  • NC_000007.13:g.44184853_44184856dup
  • NM_000162.3:c.1280_1283dup
Protein change:
R107fs
Links:
dbSNP: rs2096270699
NCBI 1000 Genomes Browser:
rs2096270699
Molecular consequence:
  • NM_000162.5:c.1280_1283dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354800.1:c.1280_1283dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354801.1:c.269_272dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354802.1:c.140_143dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354803.2:c.314_317dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_033507.3:c.1283_1286dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_033508.3:c.1277_1280dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV004102853ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)		Likely pathogenic
(Nov 3, 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, SCV004102853.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1280_1283dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 429 (NM_000162.5), adding 31 novel amino acids before encountering a stop codon (p.(Arg429AlafsTer31)). 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 diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1280_1283dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting.

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

Last Updated: May 7, 2024