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NM_000162.5(GCK):c.1133C>A (p.Ala378Asp) AND Maturity-onset diabetes of the young type 2

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 22, 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:
RCV003445468.1

Allele description [Variation Report for NM_000162.5(GCK):c.1133C>A (p.Ala378Asp)]

NM_000162.5(GCK):c.1133C>A (p.Ala378Asp)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1133C>A (p.Ala378Asp)
Other names:
NM_001354803.2:c.167C>A
HGVS:
  • NC_000007.14:g.44145617G>T
  • NG_008847.2:g.57554C>A
  • NM_000162.5:c.1133C>AMANE SELECT
  • NM_001354800.1:c.1133C>A
  • NM_001354801.1:c.122C>A
  • NM_001354802.1:c.-8C>A
  • NM_001354803.2:c.167C>A
  • NM_033507.3:c.1136C>A
  • NM_033508.3:c.1130C>A
  • NP_000153.1:p.Ala378Asp
  • NP_001341729.1:p.Ala378Asp
  • NP_001341730.1:p.Ala41Asp
  • NP_001341732.1:p.Ala56Asp
  • NP_277042.1:p.Ala379Asp
  • NP_277043.1:p.Ala377Asp
  • LRG_1074t1:c.1133C>A
  • LRG_1074t2:c.1136C>A
  • LRG_1074:g.57554C>A
  • LRG_1074p1:p.Ala378Asp
  • LRG_1074p2:p.Ala379Asp
  • NC_000007.13:g.44185216G>T
Protein change:
A377D
Molecular consequence:
  • NM_001354802.1:c.-8C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000162.5:c.1133C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1133C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.122C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.167C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1136C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1130C>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
SCV004174248ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)		Pathogenic
(Nov 22, 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, SCV004174248.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1133C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to aspartic acid at codon 378 (p.(Ala378Asp)) 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 0.984, 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 5-6 unrelated individuals with hyperglycemia (PS4; internal lab contributors). The variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mol/L and HbA1c 5.6-7.6% and three-generation, dominant family history of diabetes or hyperglycemia (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). Two other missense variants, c.1133C>T (p.Ala378Val) and c.1132G>A (p.Ala378Thr) have been interpreted as pathogenic by the ClinGen MDEP, and p.Ala378Asp has an greater Grantham distance than p.Ala378Val and p.Ala378Thr (PM5_Strong). In summary, this variant meets the criteria to be classified as pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PS4_moderate, PM5_Strong.

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

Last Updated: Jan 6, 2024