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NM_000162.5(GCK):c.766G>A (p.Glu256Lys) AND Maturity onset diabetes mellitus in young

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 12, 2019
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:
RCV004547644.1

Allele description [Variation Report for NM_000162.5(GCK):c.766G>A (p.Glu256Lys)]

NM_000162.5(GCK):c.766G>A (p.Glu256Lys)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.766G>A (p.Glu256Lys)
HGVS:
  • NC_000007.14:g.44147747C>T
  • NG_008847.2:g.55424G>A
  • NM_000162.5:c.766G>AMANE SELECT
  • NM_001354800.1:c.766G>A
  • NM_033507.3:c.769G>A
  • NM_033508.3:c.763G>A
  • NP_000153.1:p.Glu256Lys
  • NP_001341729.1:p.Glu256Lys
  • NP_277042.1:p.Glu257Lys
  • NP_277043.1:p.Glu255Lys
  • LRG_1074t1:c.766G>A
  • LRG_1074t2:c.769G>A
  • LRG_1074:g.55424G>A
  • LRG_1074p1:p.Glu256Lys
  • LRG_1074p2:p.Glu257Lys
  • NC_000007.13:g.44187346C>T
  • NM_000162.3:c.766G>A
  • P35557:p.Glu256Lys
  • p.GLU256LYS
Protein change:
E255K
Links:
UniProtKB: P35557#VAR_003706; dbSNP: rs769268803
NCBI 1000 Genomes Browser:
rs769268803
Molecular consequence:
  • NM_000162.5:c.766G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.766G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.769G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.763G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Maturity onset diabetes mellitus in young (MODY)
Synonyms:
Mason type diabetes
Identifiers:
MONDO: MONDO:0018911; MedGen: C0342276; Orphanet: 552; OMIM: 606391; Human Phenotype Ontology: HP:0004904

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005043520Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Sep 12, 2019) 		germlineclinical testing

PubMed (9)
[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

Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain.

Estalella I, Rica I, Perez de Nanclares G, Bilbao JR, Vazquez JA, San Pedro JI, Busturia MA, Castaño L; Spanish MODY Group..

Clin Endocrinol (Oxf). 2007 Oct;67(4):538-46. Epub 2007 Jun 15.

PubMed [citation]
PMID:
17573900

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
See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV005043520.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

The p.E256K pathogenic mutation (also known as c.766G>A), located in coding exon 7 of the GCK gene, results from a G to A substitution at nucleotide position 766. The glutamic acid at codon 256 is replaced by lysine, an amino acid with similar properties. This mutation has been reported in multiple individuals and families with maturity-onset diabetes of the young (MODY) (Estalella I et al. Clin. Endocrinol. (Oxf), 2007 Oct;67:538-46; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Irgens HU et al. Diabetologia, 2013 Jul;56:1512-9). Based on structural analysis, this variant is anticipated to disrupt glucose binding, resulting in reduced activity (Pilkis SJ et al. J. Biol. Chem., 1994 Sep;269:21925-8; Petit P et al. Acta Crystallogr. D Biol. Crystallogr., 2011 Nov;67:929-35; Yellapu NK et al. Biotechnol Res Int, 2013 Feb;2013:264793). Functional studies have illustrated this, by showing that E256K mutant protein has significantly reduced enzymatic activity (Gidh-Jain M et al. Proc. Natl. Acad. Sci. U.S.A., 1993 Mar;90:1932-6; Molnes J et al. FEBS J., 2008 May;275:2467-81). In addition, another alteration at the same codon, p.E256D, has been reported to cause MODY (Garin I et al. Clin. Endocrinol. (Oxf), 2008 Jun;68:873-8). Based on the supporting evidence, p.E256K is interpreted as a disease-causing mutation.

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

Last Updated: Sep 29, 2024