NM_000162.5(GCK):c.1346_1362del (p.Ala449fs) AND Monogenic diabetes

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 24, 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:: RCV003313356.1

Allele description [Variation Report for NM_000162.5(GCK):c.1346_1362del (p.Ala449fs)]

NM_000162.5(GCK):c.1346_1362del (p.Ala449fs)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1346_1362del (p.Ala449fs)

Other names:

NM_001354803.2:c.380_396del

HGVS:

NC_000007.14:g.44145176_44145192del
NG_008847.2:g.57983_57999del
NM_000162.5:c.1346_1362delMANE SELECT
NM_001354800.1:c.1346_1362del
NM_001354801.1:c.335_351del
NM_001354802.1:c.206_222del
NM_001354803.2:c.380_396del
NM_033507.3:c.1349_1365del
NM_033508.3:c.1343_1359del
NP_000153.1:p.Ala449fs
NP_001341729.1:p.Ala449fs
NP_001341730.1:p.Ala112fs
NP_001341731.1:p.Ala69fs
NP_001341732.1:p.Ala127fs
NP_277042.1:p.Ala450fs
NP_277043.1:p.Ala448fs
LRG_1074t1:c.1346_1362del
LRG_1074t2:c.1349_1365del
LRG_1074:g.57983_57999del
LRG_1074p1:p.Ala449fs
LRG_1074p2:p.Ala450fs
NC_000007.13:g.44184775_44184791del

Protein change:

A112fs

Molecular consequence:

NM_000162.5:c.1346_1362del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354800.1:c.1346_1362del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354801.1:c.335_351del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354802.1:c.206_222del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354803.2:c.380_396del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033507.3:c.1349_1365del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033508.3:c.1343_1359del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

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LOC110634714 [Hevea brasiliensis]
LOC110634714 [Hevea brasiliensis]
Gene ID:110634714

Gene
TM7SF2 [Gracilinanus agilis]
TM7SF2 [Gracilinanus agilis]
Gene ID:123251494

Gene
mgat4a [Seriola dumerili]
mgat4a [Seriola dumerili]
Gene ID:111218149

Gene
CDH13 [Papio anubis]
CDH13 [Papio anubis]
Gene ID:101007207

Gene
AACS [Pan paniscus]
AACS [Pan paniscus]
Gene ID:100983892

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004012128	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Diabetes ACMG Specifications GCK V1.2.0)	Pathogenic (Jun 24, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004012128

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)

Pathogenic
(Jun 24, 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, SCV004012128.1

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

Description

The c.1346_1362del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 449 (NM_000162.5), adding 4 novel amino acids before encountering a stop codon (p.(Ala449GlyfsTer4)). 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; PMID: 19790256). This variant is absent in gnomAD (PM2_Supporting). This variant was identified in 5 unrelated individuals with a clinical picture consistent with non-autoimmune/insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4_Moderate, internal lab contributors). This variant segregated with disease with 2 informative meioses in 2 families with MODY (PP1; internal lab contributors). In summary, the c.1346_1362del variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PP4, PS4_Moderate, PP1, 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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