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NM_000162.5(GCK):c.1130G>T (p.Arg377Leu) AND Monogenic diabetes

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 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:
RCV003330325.2

Allele description [Variation Report for NM_000162.5(GCK):c.1130G>T (p.Arg377Leu)]

NM_000162.5(GCK):c.1130G>T (p.Arg377Leu)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1130G>T (p.Arg377Leu)
Other names:
NM_000162.5(GCK):c.1130G>T; p.Arg377Leu
HGVS:
  • NC_000007.14:g.44145620C>A
  • NG_008847.2:g.57551G>T
  • NM_000162.3:c.1130G>T
  • NM_000162.5:c.1130G>TMANE SELECT
  • NM_001354800.1:c.1130G>T
  • NM_001354801.1:c.119G>T
  • NM_001354802.1:c.-11G>T
  • NM_001354803.2:c.164G>T
  • NM_033507.3:c.1133G>T
  • NM_033508.3:c.1127G>T
  • NP_000153.1:p.Arg377Leu
  • NP_001341729.1:p.Arg377Leu
  • NP_001341730.1:p.Arg40Leu
  • NP_001341732.1:p.Arg55Leu
  • NP_277042.1:p.Arg378Leu
  • NP_277043.1:p.Arg376Leu
  • LRG_1074t1:c.1130G>T
  • LRG_1074t2:c.1133G>T
  • LRG_1074:g.57551G>T
  • LRG_1074p1:p.Arg377Leu
  • LRG_1074p2:p.Arg378Leu
  • NC_000007.13:g.44185219C>A
Protein change:
R376L
Links:
dbSNP: rs193922264
NCBI 1000 Genomes Browser:
rs193922264
Molecular consequence:
  • NM_001354802.1:c.-11G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000162.5:c.1130G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1130G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.119G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.164G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1133G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1127G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004037463ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)		Likely pathogenic
(Nov 24, 2023) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004037463.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1130G>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to leucine at codon 377 (p.(Arg377Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, 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 five unrelated individuals with hyperglycemia (PS4_Moderate: PMIDs: 21348868, 30245511, internal lab contributors). At least two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L or negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.1129C>T p.(Arg377Cys), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Arg377Leu). Another missense variant, c.1129C>A p.Arg377Ser, has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023) : PS4_Moderate, PP2, PP3, PM2_Supporting, PP4_Moderate, PM5_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024