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NM_000162.5(GCK):c.1190G>A (p.Arg397His) AND Maturity-onset diabetes of the young type 2

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Sep 8, 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:
RCV003330326.1

Allele description [Variation Report for NM_000162.5(GCK):c.1190G>A (p.Arg397His)]

NM_000162.5(GCK):c.1190G>A (p.Arg397His)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1190G>A (p.Arg397His)
Other names:
NM_000162.5(GCK):c.1190G>A; p.Arg397His
HGVS:
  • NC_000007.14:g.44145560C>T
  • NG_008847.2:g.57611G>A
  • NM_000162.5:c.1190G>AMANE SELECT
  • NM_001354800.1:c.1190G>A
  • NM_001354801.1:c.179G>A
  • NM_001354802.1:c.50G>A
  • NM_001354803.2:c.224G>A
  • NM_033507.3:c.1193G>A
  • NM_033508.3:c.1187G>A
  • NP_000153.1:p.Arg397His
  • NP_001341729.1:p.Arg397His
  • NP_001341730.1:p.Arg60His
  • NP_001341731.1:p.Arg17His
  • NP_001341732.1:p.Arg75His
  • NP_277042.1:p.Arg398His
  • NP_277043.1:p.Arg396His
  • LRG_1074t1:c.1190G>A
  • LRG_1074t2:c.1193G>A
  • LRG_1074:g.57611G>A
  • LRG_1074p1:p.Arg397His
  • LRG_1074p2:p.Arg398His
  • NC_000007.13:g.44185159C>T
  • NM_000162.3:c.1190G>A
Protein change:
R17H
Links:
dbSNP: rs193929375
NCBI 1000 Genomes Browser:
rs193929375
Molecular consequence:
  • NM_000162.5:c.1190G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1190G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.179G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354802.1:c.50G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.224G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1193G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1187G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Maturity-onset diabetes of the young type 2
Synonyms:
MODY type 2; Diabetes mellitus MODY type 2; MODY glucokinase-related; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007453; MedGen: C0342277; Orphanet: 552; OMIM: 125851

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004037467ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)		Likely pathogenic
(Sep 8, 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, SCV004037467.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1190G>A variant in the glucokinase gene, GCK, causes an amino acid change of Arg to His at codon 397 (p.(Arg397His)) of NM_000162.5. Another missense variant, c.1190G>T p.Arg397Leu, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg397His (PM5_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 absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.779 which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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%) (PP4; internal lab contributors). This variant was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with 2 informative meioses in 2 families with MODY (PP1; internal lab contributors). In summary, c.1190G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5_Supporting, PP2, PM2_Supporting, PP3, PP4, PS4_Moderate, PP1.

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

Last Updated: May 7, 2024