NM_000162.5(GCK):c.1307_1319del (p.Ile436fs) AND Maturity-onset diabetes of the young type 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 20, 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:: RCV003313354.1

Allele description [Variation Report for NM_000162.5(GCK):c.1307_1319del (p.Ile436fs)]

NM_000162.5(GCK):c.1307_1319del (p.Ile436fs)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1307_1319del (p.Ile436fs)

Other names:

NM_001354803.2:c.341_353del

HGVS:

NC_000007.14:g.44145217_44145229del
NG_008847.2:g.57944_57956del
NM_000162.5:c.1307_1319delMANE SELECT
NM_001354800.1:c.1307_1319del
NM_001354801.1:c.296_308del
NM_001354802.1:c.167_179del
NM_001354803.2:c.341_353del
NM_033507.3:c.1310_1322del
NM_033508.3:c.1304_1316del
NP_000153.1:p.Ile436fs
NP_001341729.1:p.Ile436fs
NP_001341730.1:p.Ile99fs
NP_001341731.1:p.Ile56fs
NP_001341732.1:p.Ile114fs
NP_277042.1:p.Ile437fs
NP_277043.1:p.Ile435fs
LRG_1074t1:c.1307_1319del
LRG_1074t2:c.1310_1322del
LRG_1074:g.57944_57956del
LRG_1074p1:p.Ile436fs
LRG_1074p2:p.Ile437fs
NC_000007.13:g.44184816_44184828del

Protein change:

I114fs

Molecular consequence:

NM_000162.5:c.1307_1319del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354800.1:c.1307_1319del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354801.1:c.296_308del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354802.1:c.167_179del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354803.2:c.341_353del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033507.3:c.1310_1322del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033508.3:c.1304_1316del - 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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LOC100816642 [Glycine max]
LOC100816642 [Glycine max]
Gene ID:100816642

Gene
ANXA5 [Rana temporaria]
ANXA5 [Rana temporaria]
Gene ID:120918635

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004012120	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Diabetes ACMG Specifications GCK V1.2.0)	Likely pathogenic (Jun 20, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004012120

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)

Likely pathogenic
(Jun 20, 2023)

germline

curation

Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004012120.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.1307_1319del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 436 (NM_000162.5), adding 174 novel amino acids before encountering a stop codon (p.(Ile436SerfsTer174)). 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 diabetes; however, PP4 is unable to be evaluated due to lack of clinical information (internal lab contributors). In summary, c.1307_1319del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 29, 2023

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