NM_000162.5(GCK):c.167A>C (p.Lys56Thr) 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:: RCV003493961.1

Allele description [Variation Report for NM_000162.5(GCK):c.167A>C (p.Lys56Thr)]

NM_000162.5(GCK):c.167A>C (p.Lys56Thr)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.167A>C (p.Lys56Thr)

Other names:

NM_000162.5(GCK):c.167A>C; p.Lys56Thr

HGVS:

NC_000007.14:g.44153342T>G
NG_008847.2:g.49829A>C
NM_000162.5:c.167A>CMANE SELECT
NM_001354800.1:c.167A>C
NM_033507.3:c.170A>C
NM_033508.3:c.164A>C
NP_000153.1:p.Lys56Thr
NP_001341729.1:p.Lys56Thr
NP_277042.1:p.Lys57Thr
NP_277043.1:p.Lys55Thr
LRG_1074t1:c.167A>C
LRG_1074t2:c.170A>C
LRG_1074:g.49829A>C
LRG_1074p1:p.Lys56Thr
LRG_1074p2:p.Lys57Thr
NC_000007.13:g.44192941T>G
NM_000162.3:c.167A>C

Protein change:

K55T

Molecular consequence:

NM_000162.5:c.167A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.167A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.170A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.164A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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LOC110625113 [Manihot esculenta]
LOC110625113 [Manihot esculenta]
Gene ID:110625113

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004242341	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

SCV004242341

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

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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, SCV004242341.1

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

Description

The c.167A>C variant in the glucokinase gene, GCK, causes an amino acid change of lysine to threonine at codon 56 (p.(Lys56Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 33852230, ClinVar VCV001807279.3, Internal lab contributors). In summary, c.167A>C 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, approved 8/11/2023): PP4_Moderate, PP2, PP3, PP1_Moderate, PM2_Supporting, PS4_Moderate.

#	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: Sep 29, 2024

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