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NM_000162.5(GCK):c.617C>T (p.Thr206Met) AND Monogenic diabetes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 11, 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:
RCV002271659.2

Allele description [Variation Report for NM_000162.5(GCK):c.617C>T (p.Thr206Met)]

NM_000162.5(GCK):c.617C>T (p.Thr206Met)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.617C>T (p.Thr206Met)
HGVS:
  • NC_000007.14:g.44149822G>A
  • NG_008847.2:g.53349C>T
  • NM_000162.5:c.617C>TMANE SELECT
  • NM_001354800.1:c.617C>T
  • NM_033507.3:c.620C>T
  • NM_033508.3:c.614C>T
  • NP_000153.1:p.Thr206Met
  • NP_001341729.1:p.Thr206Met
  • NP_277042.1:p.Thr207Met
  • NP_277043.1:p.Thr205Met
  • LRG_1074t1:c.617C>T
  • LRG_1074t2:c.620C>T
  • LRG_1074:g.53349C>T
  • LRG_1074p1:p.Thr206Met
  • LRG_1074p2:p.Thr207Met
  • NC_000007.13:g.44189421G>A
  • NM_000162.3:c.617C>T
Protein change:
T205M
Links:
dbSNP: rs1441649062
NCBI 1000 Genomes Browser:
rs1441649062
Molecular consequence:
  • NM_000162.5:c.617C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.617C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.620C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.614C>T - 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
SCV002555833Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jun 11, 2022) 		germlineclinical testing

PubMed (10)
[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

High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI.

Massa O, Meschi F, Cuesta-Munoz A, Caumo A, Cerutti F, Toni S, Cherubini V, Guazzarotti L, Sulli N, Matschinsky FM, Lorini R, Iafusco D, Barbetti F; Diabetes Study Group of the Italian Society of Paediatic Endocrinology and Diabetes (SIEDP)..

Diabetologia. 2001 Jul;44(7):898-905.

PubMed [citation]
PMID:
11508276

A new missense mutation in the glucokinase gene in an Italian Mody family.

Bertini C, Maioli M, Fresu P, Tonolo G, Pirastu M, Maioli M.

Diabetologia. 1996 Nov;39(11):1413-4. No abstract available.

PubMed [citation]
PMID:
8933019
See all PubMed Citations (10)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002555833.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

Variant summary: GCK c.617C>T (p.Thr206Met) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Five 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 251436 control chromosomes. c.617C>T has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young (example, Galan_2006, Kavvoura_2014, Aloi_2017, Gaal_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Galan_2006). The most pronounced variant effect results in lowered substrate affinity for glucose indicating a loss of cooperativity for glucose as a substrate and a severely diminished catalytic constant. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. 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

Last Updated: Oct 20, 2024