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NM_000162.5(GCK):c.768G>C (p.Glu256Asp) AND Maturity-onset diabetes of the young type 2

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jul 9, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000029918.3

Allele description [Variation Report for NM_000162.5(GCK):c.768G>C (p.Glu256Asp)]

NM_000162.5(GCK):c.768G>C (p.Glu256Asp)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.768G>C (p.Glu256Asp)
HGVS:
  • NC_000007.14:g.44147745C>G
  • NG_008847.2:g.55426G>C
  • NM_000162.5:c.768G>CMANE SELECT
  • NM_001354800.1:c.768G>C
  • NM_033507.3:c.771G>C
  • NM_033508.3:c.765G>C
  • NP_000153.1:p.Glu256Asp
  • NP_001341729.1:p.Glu256Asp
  • NP_277042.1:p.Glu257Asp
  • NP_277043.1:p.Glu255Asp
  • LRG_1074t1:c.768G>C
  • LRG_1074t2:c.771G>C
  • LRG_1074:g.55426G>C
  • LRG_1074p1:p.Glu256Asp
  • LRG_1074p2:p.Glu257Asp
  • NC_000007.13:g.44187344C>G
  • NM_000162.3:c.768G>C
Protein change:
E255D
Links:
dbSNP: rs193922328
NCBI 1000 Genomes Browser:
rs193922328
Molecular consequence:
  • NM_000162.5:c.768G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.768G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.771G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.765G>C - 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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000052573Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely pathogenic
(Jul 9, 2024) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Haploinsufficiency at GCK gene is not a frequent event in MODY2 patients.

Garin I, Rica I, Estalella I, Oyarzabal M, Rodríguez-Rigual M, San Pedro JI, Pérez-Nanclares G, Fernández-Rebollo E, Busturia MA, Castaño L, Pérez de Nanclares G; Spanish MODY Group..

Clin Endocrinol (Oxf). 2008 Jun;68(6):873-8. doi: 10.1111/j.1365-2265.2008.03214.x. Epub 2008 Feb 1.

PubMed [citation]
PMID:
18248649

Analysis of the GCK gene in 79 MODY type 2 patients: A multicenter Turkish study, mutation profile and description of twenty novel mutations.

Aykut A, Karaca E, Onay H, Gökşen D, Çetinkalp Ş, Eren E, Ersoy B, Çakır EP, Büyükinan M, Kara C, Anık A, Kırel B, Özen S, Atik T, Darcan Ş, Özkınay F.

Gene. 2018 Jan 30;641:186-189. doi: 10.1016/j.gene.2017.10.057. Epub 2017 Oct 19.

PubMed [citation]
PMID:
29056535

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052573.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: GCK c.768G>C (p.Glu256Asp) results in a 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 was absent in 251142 control chromosomes (gnomAD). c.768G>C has been reported in the literature in at least an individual affected with autosomal dominant maturity onset diabetes of the young 2/neonatal diabetes mellitus (examples: Garin_2008, Aykut_2018). These data indicate that the variant is likely associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.766G>A, p.Glu256Lys), supporting the critical relevance of codon 256 to GCK protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29056535, 18248649). ClinVar contains an entry for this variant (Variation ID: 36255). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Sep 29, 2024