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NM_000162.5(GCK):c.1378del (p.Ala460fs) AND Maturity-onset diabetes of the young type 2

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 18, 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:
RCV003313365.1

Allele description [Variation Report for NM_000162.5(GCK):c.1378del (p.Ala460fs)]

NM_000162.5(GCK):c.1378del (p.Ala460fs)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1378del (p.Ala460fs)
Other names:
NM_001354803.2:c.412del
HGVS:
  • NC_000007.14:g.44145157del
  • NG_008847.2:g.58015del
  • NM_000162.5:c.1378delMANE SELECT
  • NM_001354800.1:c.1369+9del
  • NM_001354801.1:c.367del
  • NM_001354802.1:c.229+9del
  • NM_001354803.2:c.412del
  • NM_033507.3:c.1381del
  • NM_033508.3:c.1375del
  • NP_000153.1:p.Ala460fs
  • NP_001341730.1:p.Ala123fs
  • NP_001341732.1:p.Ala138fs
  • NP_277042.1:p.Ala461fs
  • NP_277043.1:p.Ala459fs
  • LRG_1074t1:c.1378del
  • LRG_1074t2:c.1381del
  • LRG_1074:g.58015del
  • LRG_1074p1:p.Ala460fs
  • LRG_1074p2:p.Ala461fs
  • NC_000007.13:g.44184756del
Protein change:
A123fs
Molecular consequence:
  • NM_000162.5:c.1378del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354801.1:c.367del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354803.2:c.412del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_033507.3:c.1381del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_033508.3:c.1375del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354800.1:c.1369+9del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354802.1:c.229+9del - intron variant - [Sequence Ontology: SO:0001627]

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
SCV004012140ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)		Pathogenic
(Jun 18, 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, SCV004012140.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1378del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 460 (NM_000162.5), adding 154 novel amino acids before encountering a stop codon (p.(Ala460ProfsTer154)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss-of-function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). 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 antibody negative) (PP4_Moderate; PMID: 15841481). In summary, c.1378del 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_Moderate.

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

Last Updated: Jul 29, 2023