NM_000162.5(GCK):c.1064T>C (p.Leu355Pro) AND Monogenic diabetes

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 18, 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:: RCV003318506.1

Allele description [Variation Report for NM_000162.5(GCK):c.1064T>C (p.Leu355Pro)]

NM_000162.5(GCK):c.1064T>C (p.Leu355Pro)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1064T>C (p.Leu355Pro)

Other names:

NM_000162.5(GCK):c.1064T>C; p.Leu355Pro

HGVS:

NC_000007.14:g.44145686A>G
NG_008847.2:g.57485T>C
NM_000162.5:c.1064T>CMANE SELECT
NM_001354800.1:c.1064T>C
NM_001354801.1:c.53T>C
NM_001354802.1:c.-77T>C
NM_001354803.2:c.98T>C
NM_033507.3:c.1067T>C
NM_033508.3:c.1061T>C
NP_000153.1:p.Leu355Pro
NP_001341729.1:p.Leu355Pro
NP_001341730.1:p.Leu18Pro
NP_001341732.1:p.Leu33Pro
NP_277042.1:p.Leu356Pro
NP_277043.1:p.Leu354Pro
LRG_1074t1:c.1064T>C
LRG_1074t2:c.1067T>C
LRG_1074:g.57485T>C
LRG_1074p1:p.Leu355Pro
LRG_1074p2:p.Leu356Pro
NC_000007.13:g.44185285A>G
NM_000162.3:c.1064T>C

Protein change:

L18P

Links:

dbSNP: rs1583592156

NCBI 1000 Genomes Browser:

rs1583592156

Molecular consequence:

NM_001354802.1:c.-77T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000162.5:c.1064T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.1064T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354801.1:c.53T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354803.2:c.98T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.1067T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.1061T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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glycosyltransferase, partial [Arabidopsis thaliana]
glycosyltransferase, partial [Arabidopsis thaliana]
gi|591402164|gb|AHL38809.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004022330	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Diabetes ACMG Specifications GCK V1.2.0)	Uncertain significance (Jul 18, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004022330

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)

Uncertain significance
(Jul 18, 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, SCV004022330.1

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

Description

The c.1064T>C variant in the glucokinase gene, GCK, causes an amino acid change of Leucine to Proline at codon 355 (p.(Leu355Pro)) 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 0.9689, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, as well as in two individuals in ClinVar whose clinical status was not known DOI:10.1055/s-2004-819152, ClinVar ID 804832, internal lab contributor). However, PS4_Moderate cannot be applied because the number of affected individuals is below the ClinGen MDEP threshold. This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, the evidence supports the classification of c.1064T>C as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP4_Moderate, PP2, PP3, 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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