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NM_000162.5(GCK):c.1190G>T (p.Arg397Leu) AND Monogenic diabetes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 16, 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:
RCV003318494.1

Allele description [Variation Report for NM_000162.5(GCK):c.1190G>T (p.Arg397Leu)]

NM_000162.5(GCK):c.1190G>T (p.Arg397Leu)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1190G>T (p.Arg397Leu)
Other names:
NM_000162.5(GCK):c.1190G>T; p.Arg397Leu
HGVS:
  • NC_000007.14:g.44145560C>A
  • NG_008847.2:g.57611G>T
  • NM_000162.5:c.1190G>TMANE SELECT
  • NM_001354800.1:c.1190G>T
  • NM_001354801.1:c.179G>T
  • NM_001354802.1:c.50G>T
  • NM_001354803.2:c.224G>T
  • NM_033507.3:c.1193G>T
  • NM_033508.3:c.1187G>T
  • NP_000153.1:p.Arg397Leu
  • NP_001341729.1:p.Arg397Leu
  • NP_001341730.1:p.Arg60Leu
  • NP_001341731.1:p.Arg17Leu
  • NP_001341732.1:p.Arg75Leu
  • NP_277042.1:p.Arg398Leu
  • NP_277043.1:p.Arg396Leu
  • LRG_1074t1:c.1190G>T
  • LRG_1074t2:c.1193G>T
  • LRG_1074:g.57611G>T
  • LRG_1074p1:p.Arg397Leu
  • LRG_1074p2:p.Arg398Leu
  • NC_000007.13:g.44185159C>A
  • NM_000162.3:c.1190G>T
  • p.ARG397LEU
Protein change:
R17L
Links:
dbSNP: rs193929375
NCBI 1000 Genomes Browser:
rs193929375
Molecular consequence:
  • NM_000162.5:c.1190G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1190G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.179G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354802.1:c.50G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.224G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1193G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1187G>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
SCV004022327ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)		Pathogenic
(Jul 16, 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, SCV004022327.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1190G>T variant in the glucokinase gene, GCK, causes an amino acid change of Arg to Leu at codon 397 (p.(Arg397Leu)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.925 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:17186219 , internal lab contributors). This variant segregated with diabetes, with at least 7 informative meioses in 14 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L, HbA1c 5.6 - 7.6%, and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:17186219). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Arg397Leu has RAI=0.72, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 17186219). This variant has been detected in the homozygous state in at least 5 individuals with neonatal diabetes (PM3; internal lab contributors). In summary, c.1190G>T 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): PM2_Supporting, PP2, PP3, PS4, PP1_Strong, PP4_Moderate, PS3_Supporting, PM3.

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

Last Updated: May 7, 2024