NM_000162.5(GCK):c.1303_1306dup (p.Ile436fs) AND Maturity-onset diabetes of the young type 2

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 8, 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:: RCV003330369.1

Allele description [Variation Report for NM_000162.5(GCK):c.1303_1306dup (p.Ile436fs)]

NM_000162.5(GCK):c.1303_1306dup (p.Ile436fs)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1303_1306dup (p.Ile436fs)

Other names:

NM_001354803.2:c.337_340dup

HGVS:

NC_000007.14:g.44145228TC[4]
NG_008847.2:g.57940GA[4]
NM_000162.5:c.1303_1306dupMANE SELECT
NM_001354800.1:c.1303_1306dup
NM_001354801.1:c.292_295dup
NM_001354802.1:c.163_166dup
NM_001354803.2:c.337_340dup
NM_033507.3:c.1306_1309dup
NM_033508.3:c.1300_1303dup
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.1303_1306dup
LRG_1074t2:c.1306_1309dup
LRG_1074:g.57940GA[4]
LRG_1074p1:p.Ile436fs
LRG_1074p2:p.Ile437fs
NC_000007.13:g.44184827TC[4]
NC_000007.14:g.44145228_44145231dup

Protein change:

I114fs

Molecular consequence:

NM_000162.5:c.1303_1306dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354800.1:c.1303_1306dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354801.1:c.292_295dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354802.1:c.163_166dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354803.2:c.337_340dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033507.3:c.1306_1309dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033508.3:c.1300_1303dup - 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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LOC100788761 [Glycine max]
LOC100788761 [Glycine max]
Gene ID:100788761

Gene
LOC107459705 [Arachis duranensis]
LOC107459705 [Arachis duranensis]
Gene ID:107459705

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004037464	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)	Likely pathogenic (Sep 8, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004037464

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)

Likely pathogenic
(Sep 8, 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, SCV004037464.1

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

Description

The c.1303_1306dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 436 (NM_000162.5), adding 24 novel amino acids before encountering a stop codon (p.(Ile436ArgfsTer24)). 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 consistent with GCK-MODY, but there was insufficient clinical information to evaluate for PP4 (internal lab contributors). In summary, c.1303_1306dup 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.

#	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: Oct 7, 2023

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