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NM_000162.5(GCK):c.775G>A (p.Ala259Thr) AND Monogenic diabetes

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Aug 12, 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:
RCV002282182.3

Allele description [Variation Report for NM_000162.5(GCK):c.775G>A (p.Ala259Thr)]

NM_000162.5(GCK):c.775G>A (p.Ala259Thr)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.775G>A (p.Ala259Thr)
Other names:
NM_000162.5(GCK):c.775G>A; p.Ala259Thr
HGVS:
  • NC_000007.14:g.44147738C>T
  • NG_008847.2:g.55433G>A
  • NM_000162.5:c.775G>AMANE SELECT
  • NM_001354800.1:c.775G>A
  • NM_033507.3:c.778G>A
  • NM_033508.3:c.772G>A
  • NP_000153.1:p.Ala259Thr
  • NP_001341729.1:p.Ala259Thr
  • NP_277042.1:p.Ala260Thr
  • NP_277043.1:p.Ala258Thr
  • LRG_1074t1:c.775G>A
  • LRG_1074t2:c.778G>A
  • LRG_1074:g.55433G>A
  • LRG_1074p1:p.Ala259Thr
  • LRG_1074p2:p.Ala260Thr
  • NC_000007.13:g.44187337C>T
  • NM_000162.3:c.775G>A
Protein change:
A258T
Links:
dbSNP: rs1375656631
NCBI 1000 Genomes Browser:
rs1375656631
Molecular consequence:
  • NM_000162.5:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.775G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.778G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.772G>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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002572107Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Aug 18, 2022) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV004032086ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)		Pathogenic
(Aug 12, 2023) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity.

Hattersley AT.

Diabet Med. 1998 Jan;15(1):15-24. Review. Erratum in: Diabet Med 1998 May;15(5):437.

PubMed [citation]
PMID:
9472859

Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY).

Thomson KL, Gloyn AL, Colclough K, Batten M, Allen LI, Beards F, Hattersley AT, Ellard S.

Hum Mutat. 2003 Nov;22(5):417.

PubMed [citation]
PMID:
14517956
See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002572107.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Variant summary: GCK c.775G>A (p.Ala259Thr) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251106 control chromosomes. c.775G>A has been reported in the literature in multiple individuals affected with Monogenic Diabetes, specifically features of Maturity Onset Diabetes of the Young (MODY2) (example, Hattersley_1998, Matyka_1998, Thomson_2003, Lukasova_208, Capuano_2012, Tatsi_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

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

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004032086.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.775G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 259 (p.(Ala259Thr)) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and 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). Another missense variant, c.776C>T, p.Ala259Val, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ala259Thr (PM5_Supporting). This variant was identified in 12 unrelated individuals with hyperglycemia (PS4; internal lab contributors). Additionally, this variant segregated with diabetes/hyperglycemia, with 7 informative meioses in 6 families (PP1_Strong; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and a 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, c.775G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP3, PP2, PM5_Supporting, PS4, PP1_Strong, PP4_Moderate, PM2_Supporting.

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

Last Updated: Sep 29, 2024