NM_000162.5(GCK):c.1368del (p.Cys457fs) AND Monogenic diabetes

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 19, 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:: RCV003313373.1

Allele description [Variation Report for NM_000162.5(GCK):c.1368del (p.Cys457fs)]

NM_000162.5(GCK):c.1368del (p.Cys457fs)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1368del (p.Cys457fs)

Other names:

NM_001354803.2:c.402del

HGVS:

NC_000007.14:g.44145167del
NG_008847.2:g.58005del
NM_000162.5:c.1368delMANE SELECT
NM_001354800.1:c.1368del
NM_001354801.1:c.357del
NM_001354802.1:c.228del
NM_001354803.2:c.402del
NM_033507.3:c.1371del
NM_033508.3:c.1365del
NP_000153.1:p.Cys457fs
NP_001341729.1:p.Ter457AspextTer?
NP_001341730.1:p.Cys120fs
NP_001341731.1:p.Ter77AspextTer?
NP_001341732.1:p.Cys135fs
NP_277042.1:p.Cys458fs
NP_277043.1:p.Cys456fs
LRG_1074t1:c.1368del
LRG_1074t2:c.1371del
LRG_1074:g.58005del
LRG_1074p1:p.Cys457fs
LRG_1074p2:p.Cys458fs
NC_000007.13:g.44184766del

Protein change:

C120fs

Molecular consequence:

NM_000162.5:c.1368del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354800.1:c.1368del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354801.1:c.357del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354802.1:c.228del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354803.2:c.402del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033507.3:c.1371del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033508.3:c.1365del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Monogenic diabetes
Identifiers:: MONDO: MONDO:0015967; MedGen: C3888631

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004012149	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Diabetes ACMG Specifications GCK V1.2.0)	Likely pathogenic (Jun 19, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004012149

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)

Likely pathogenic
(Jun 19, 2023)

germline

curation

Citation Link

Help

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, SCV004012149.1

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

Description

The c.1368del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 457 (NM_000545.6), adding 157 novel amino acids before encountering a stop codon (p.(Cys457Valfs157)). 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 from gnomAD 2.1.1 (PM2_Supporting). In summary, c.1368del 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 22, 2023

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