NM_000162.5(GCK):c.1054del (p.Ile351_Leu352insTer) AND Monogenic diabetes

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 31, 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:: RCV003993676.1

Allele description [Variation Report for NM_000162.5(GCK):c.1054del (p.Ile351_Leu352insTer)]

NM_000162.5(GCK):c.1054del (p.Ile351_Leu352insTer)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1054del (p.Ile351_Leu352insTer)

Other names:

NM_000162.5(GCK):c.1054del; p.Ile351_Leu352insTer

HGVS:

NC_000007.14:g.44145697del
NG_008847.2:g.57475del
NM_000162.5:c.1054delMANE SELECT
NM_001354800.1:c.1054del
NM_001354801.1:c.43del
NM_001354802.1:c.-87del
NM_001354803.2:c.88del
NM_033507.3:c.1057del
NM_033508.3:c.1051del
NP_000153.1:p.Ile351_Leu352insTer
NP_001341729.1:p.Ile351_Leu352insTer
NP_001341730.1:p.Ile14_Leu15insTer
NP_001341732.1:p.Ile29_Leu30insTer
NP_277042.1:p.Ile352_Leu353insTer
NP_277043.1:p.Ile350_Leu351insTer
LRG_1074t1:c.1054del
LRG_1074t2:c.1057del
LRG_1074:g.57475del
LRG_1074p1:p.Ile351_Leu352insTer
LRG_1074p2:p.Ile352_Leu353insTer
NC_000007.13:g.44185296del
NM_000162.3:c.1054del

Links:

dbSNP: rs1562713041

NCBI 1000 Genomes Browser:

rs1562713041

Molecular consequence:

NM_001354802.1:c.-87del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000162.5:c.1054del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354800.1:c.1054del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354801.1:c.43del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354803.2:c.88del - nonsense - [Sequence Ontology: SO:0001587]
NM_033507.3:c.1057del - nonsense - [Sequence Ontology: SO:0001587]
NM_033508.3:c.1051del - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

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RecName: Full=Protein phosphatase 1A; AltName: Full=Protein phosphatase 2C isofo...
RecName: Full=Protein phosphatase 1A; AltName: Full=Protein phosphatase 2C isoform alpha; Short=PP2C-alpha; AltName: Full=Protein phosphatase IA
gi|548442|sp|P35813.1|PPM1A_HUMAN

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004812205	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)	Likely pathogenic (Mar 31, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004812205

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)

Likely pathogenic
(Mar 31, 2024)

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, SCV004812205.1

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

Description

The c.1054del variant in the glucokinase gene, GCK, results in a premature termination at codon 352 (p.Leu352Ter) of NM_000162.5. 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). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1054del 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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