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NM_000162.5(GCK):c.1364T>A (p.Val455Glu) AND Maturity-onset diabetes of the young type 2

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 27, 2022
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:
RCV002469275.2

Allele description [Variation Report for NM_000162.5(GCK):c.1364T>A (p.Val455Glu)]

NM_000162.5(GCK):c.1364T>A (p.Val455Glu)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1364T>A (p.Val455Glu)
HGVS:
  • NC_000007.14:g.44145170A>T
  • NG_008847.2:g.58001T>A
  • NM_000162.5:c.1364T>AMANE SELECT
  • NM_001354800.1:c.1364T>A
  • NM_001354801.1:c.353T>A
  • NM_001354802.1:c.224T>A
  • NM_001354803.2:c.398T>A
  • NM_033507.3:c.1367T>A
  • NM_033508.3:c.1361T>A
  • NP_000153.1:p.Val455Glu
  • NP_001341729.1:p.Val455Glu
  • NP_001341730.1:p.Val118Glu
  • NP_001341731.1:p.Val75Glu
  • NP_001341732.1:p.Val133Glu
  • NP_277042.1:p.Val456Glu
  • NP_277043.1:p.Val454Glu
  • LRG_1074t1:c.1364T>A
  • LRG_1074t2:c.1367T>A
  • LRG_1074:g.58001T>A
  • LRG_1074p1:p.Val455Glu
  • LRG_1074p2:p.Val456Glu
  • NC_000007.13:g.44184769A>T
  • NM_000162.3:c.1364T>A
Protein change:
V118E
Links:
dbSNP: rs753795627
NCBI 1000 Genomes Browser:
rs753795627
Molecular consequence:
  • NM_000162.5:c.1364T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1364T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.353T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354802.1:c.224T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.398T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1367T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1361T>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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002765941Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely pathogenic
(Nov 27, 2022) 		germlineclinical testing

PubMed (7)
[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

Screening of mutations and polymorphisms in the glucokinase gene in Czech diabetic and healthy control populations.

Lukášová P, Včelák J, Vaňková M, Vejražková D, Andělová K, Bendlová B.

Physiol Res. 2008;57 Suppl 1:S99-S108. Epub 2008 Feb 13.

PubMed [citation]
PMID:
18271687

Glucokinase (GCK) and other susceptibility genes for beta-cell dysfunction: the candidate approach.

Gloyn AL, Tribble ND, van de Bunt M, Barrett A, Johnson PR.

Biochem Soc Trans. 2008 Jun;36(Pt 3):306-11. doi: 10.1042/BST0360306.

PubMed [citation]
PMID:
18481947
See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002765941.1

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

Description

Variant summary: GCK c.1364T>A (p.Val455Glu) 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 2.9e-05 in 238652 control chromosomes. c.1364T>A has been reported in the literature in individuals affected with features of Maturity Onset Diabetes Of The Young 2 (e.g. Lukasova_2008, Gloyn_2009, Colclough_2022). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function suggesting that the variant has an inactivating effect on the protein and reduces activity (e.g. Gloyn_2008, Langer_2021). The most pronounced variant effect results in 10%-<30% of normal activity (Gloyn_2008) consistent with the established molecular mechanism of disease. Four ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments, with two citing the variant as uncertain significance, one citing the variant as likely pathogenic, and one citing the variant as pathogenic. Some submitters cite overlapping, but not all inclusive evidence utilized in the context of this evaluation. 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: Aug 18, 2024