NM_000162.5(GCK):c.1331dup (p.Ser445fs) AND Monogenic diabetes

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 30, 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:: RCV003318526.1

Allele description [Variation Report for NM_000162.5(GCK):c.1331dup (p.Ser445fs)]

NM_000162.5(GCK):c.1331dup (p.Ser445fs)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1331dup (p.Ser445fs)

Other names:

NM_001354803.2:c.365dup

HGVS:

NC_000007.14:g.44145205dup
NG_008847.2:g.57968dup
NM_000162.5:c.1331dupMANE SELECT
NM_001354800.1:c.1331dup
NM_001354801.1:c.320dup
NM_001354802.1:c.191dup
NM_001354803.2:c.365dup
NM_033507.3:c.1334dup
NM_033508.3:c.1328dup
NP_000153.1:p.Ser445fs
NP_001341729.1:p.Ser445fs
NP_001341730.1:p.Ser108fs
NP_001341731.1:p.Ser65fs
NP_001341732.1:p.Ser123fs
NP_277042.1:p.Ser446fs
NP_277043.1:p.Ser444fs
LRG_1074t1:c.1331dup
LRG_1074t2:c.1334dup
LRG_1074:g.57968dup
LRG_1074p1:p.Ser445fs
LRG_1074p2:p.Ser446fs
NC_000007.13:g.44184804dup

Protein change:

S108fs

Molecular consequence:

NM_000162.5:c.1331dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354800.1:c.1331dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354801.1:c.320dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354802.1:c.191dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354803.2:c.365dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033507.3:c.1334dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033508.3:c.1328dup - 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
SCV004022342	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Diabetes ACMG Specifications GCK V1.2.0)	Likely pathogenic (Jul 30, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004022342

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)

Likely pathogenic
(Jul 30, 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, SCV004022342.1

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

Description

The c.1331dup variant in the GCK gene causes a frameshift in the protein at codon 445 (NM_000162.5), adding 14 novel amino acids before encountering a stop codon (p.(Ser445GlnfsTer14)). While this variant, located in exon 10/10, is predicted to result in a premature stop codon that is predicted to escape nonsense mediated decay, it is a functionally important region in a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in one individual with a clinical picture consistent with monogenic diabetes; however PS4_Moderate cannot be applied because this number is below the MDEP threshold (internal lab contributor). 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). This variant segregated with disease with one informative meiosis in a family with MODY; however, this does not meet the thresholds for PP1 set by Jarvik and Browning (PMID: 27236918) (internal lab contributor). In summary, c.1331dup 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: Aug 5, 2023

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