NM_000162.5(GCK):c.1133_1149del (p.Ala378fs) AND Monogenic diabetes

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 22, 2024
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:: RCV003883153.1

Allele description [Variation Report for NM_000162.5(GCK):c.1133_1149del (p.Ala378fs)]

NM_000162.5(GCK):c.1133_1149del (p.Ala378fs)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1133_1149del (p.Ala378fs)

Other names:

NM_000162.5(GCK):c.1133_1149del; p.Ala378fs

HGVS:

NC_000007.14:g.44145603_44145619del
NG_008847.2:g.57554_57570del
NM_000162.5:c.1133_1149delMANE SELECT
NM_001354800.1:c.1133_1149del
NM_001354801.1:c.122_138del
NM_001354802.1:c.-8_9del
NM_001354803.2:c.167_183del
NM_033507.3:c.1136_1152del
NM_033508.3:c.1130_1146del
NP_000153.1:p.Ala378fs
NP_001341729.1:p.Ala378fs
NP_001341730.1:p.Ala41fs
NP_001341731.1:p.Met1fs
NP_001341732.1:p.Ala56fs
NP_277042.1:p.Ala379fs
NP_277043.1:p.Ala377fs
LRG_1074t1:c.1133_1149del
LRG_1074t2:c.1136_1152del
LRG_1074:g.57554_57570del
LRG_1074p1:p.Ala378fs
LRG_1074p2:p.Ala379fs
NC_000007.13:g.44185202_44185218del

Protein change:

A377fs

Links:

dbSNP: rs1554334610

NCBI 1000 Genomes Browser:

rs1554334610

Molecular consequence:

NM_000162.5:c.1133_1149del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354800.1:c.1133_1149del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354801.1:c.122_138del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354802.1:c.-8_9del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354803.2:c.167_183del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033507.3:c.1136_1152del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033508.3:c.1130_1146del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354802.1:c.-8_9del - initiator_codon_variant - [Sequence Ontology: SO:0001582]

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
SCV004697899	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)	Likely pathogenic (Jan 22, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004697899

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)

Likely pathogenic
(Jan 22, 2024)

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, SCV004697899.1

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

Description

The c.1133_1149del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 378 (NM_000162.5), adding 75 novel amino acids before encountering a stop codon (p.(Ala378GlyfsTer75)). This variant, located in biologically-relevant exon 9 of 10, is predicted to lead to nonsense mediated decay 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). In summary, c.1133_1149del 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: May 7, 2024

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