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NM_000162.5(GCK):c.1145G>A (p.Cys382Tyr) 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:
RCV003318508.1

Allele description [Variation Report for NM_000162.5(GCK):c.1145G>A (p.Cys382Tyr)]

NM_000162.5(GCK):c.1145G>A (p.Cys382Tyr)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1145G>A (p.Cys382Tyr)
Other names:
NM_000162.5(GCK):c.1145G>A; p.Cys382Tyr
HGVS:
  • NC_000007.14:g.44145605C>T
  • NG_008847.2:g.57566G>A
  • NM_000162.5:c.1145G>AMANE SELECT
  • NM_001354800.1:c.1145G>A
  • NM_001354801.1:c.134G>A
  • NM_001354802.1:c.5G>A
  • NM_001354803.2:c.179G>A
  • NM_033507.3:c.1148G>A
  • NM_033508.3:c.1142G>A
  • NP_000153.1:p.Cys382Tyr
  • NP_001341729.1:p.Cys382Tyr
  • NP_001341730.1:p.Cys45Tyr
  • NP_001341731.1:p.Cys2Tyr
  • NP_001341732.1:p.Cys60Tyr
  • NP_277042.1:p.Cys383Tyr
  • NP_277043.1:p.Cys381Tyr
  • LRG_1074t1:c.1145G>A
  • LRG_1074t2:c.1148G>A
  • LRG_1074:g.57566G>A
  • LRG_1074p1:p.Cys382Tyr
  • LRG_1074p2:p.Cys383Tyr
  • NC_000007.13:g.44185204C>T
  • NM_000162.3:c.1145G>A
Protein change:
C2Y
Links:
dbSNP: rs2096271616
NCBI 1000 Genomes Browser:
rs2096271616
Molecular consequence:
  • NM_000162.5:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354802.1:c.5G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.179G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1148G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1142G>A - 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
SCV004022348ClinGen 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, SCV004022348.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1145G>A variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to tyrosine at codon 382 (p.(Cys382Tyr)) 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 0.922 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in the homozygous state in three individuals with neonatal diabetes and negative testing for ABCC8, KCNJ11, and INS (internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 1 family with MODY (PP1; internal lab contributors). Another missense variant, c.1144T>C p.Cys382Arg, has been interpreted as pathogenic by the ClinGen MDEP, and p.Cys382Tyr has a greater Grantham distance (PM5). This variant was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; Zubkova N.A et al, World J PM. 2017;1(1):40-48, https://doi.org/10.14341/WJPM9298, internal lab contributors). In summary, c.1145G>A 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): PP1, PP2, PP3, PM2_Supporting, PM5, PP4, PS4.

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

Last Updated: May 7, 2024