NM_000162.5(GCK):c.1240A>G (p.Lys414Glu) AND Monogenic diabetes

Clinical significance:Likely pathogenic (Last evaluated: Jan 22, 2020)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001248969.1

Allele description [Variation Report for NM_000162.5(GCK):c.1240A>G (p.Lys414Glu)]

NM_000162.5(GCK):c.1240A>G (p.Lys414Glu)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1240A>G (p.Lys414Glu)
HGVS:
  • NC_000007.14:g.44145510T>C
  • NG_008847.2:g.57661A>G
  • NM_000162.5:c.1240A>GMANE SELECT
  • NM_001354800.1:c.1240A>G
  • NM_001354801.1:c.229A>G
  • NM_001354802.1:c.100A>G
  • NM_001354803.2:c.274A>G
  • NM_033507.3:c.1243A>G
  • NM_033508.3:c.1237A>G
  • NP_000153.1:p.Lys414Glu
  • NP_001341729.1:p.Lys414Glu
  • NP_001341730.1:p.Lys77Glu
  • NP_001341731.1:p.Lys34Glu
  • NP_001341732.1:p.Lys92Glu
  • NP_277042.1:p.Lys415Glu
  • NP_277043.1:p.Lys413Glu
  • LRG_1074t1:c.1240A>G
  • LRG_1074t2:c.1243A>G
  • LRG_1074:g.57661A>G
  • LRG_1074p1:p.Lys414Glu
  • LRG_1074p2:p.Lys415Glu
  • NC_000007.13:g.44185109T>C
  • NM_000162.3(GCK):c.1240A>G
  • NM_000162.3:c.1240A>G
  • P35557:p.Lys414Glu
Protein change:
K34E
Links:
UniProtKB: P35557#VAR_003714; dbSNP: rs193922272
NCBI 1000 Genomes Browser:
rs193922272
Molecular consequence:
  • NM_000162.5:c.1240A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1240A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.229A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354802.1:c.100A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.274A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1243A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1237A>G - 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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001422801Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedLikely pathogenic
(Jan 22, 2020)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants.

Takeda J, Gidh-Jain M, Xu LZ, Froguel P, Velho G, Vaxillaire M, Cohen D, Shimada F, Makino H, Nishi S, et al.

J Biol Chem. 1993 Jul 15;268(20):15200-4.

PubMed [citation]
PMID:
8325892

Mutants of glucokinase cause hypoglycaemia- and hyperglycaemia syndromes and their analysis illuminates fundamental quantitative concepts of glucose homeostasis.

Davis EA, Cuesta-Muñoz A, Raoul M, Buettger C, Sweet I, Moates M, Magnuson MA, Matschinsky FM.

Diabetologia. 1999 Oct;42(10):1175-86.

PubMed [citation]
PMID:
10525657

Details of each submission

From Broad Institute Rare Disease Group, Broad Institute, SCV001422801.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The p.Lys414Glu variant in GCK has been reported in at least one individual with Monogenic Diabetes (PMID: 8433729), and was absent from large population studies. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36188). In vitro functional studies provide some evidence that the p.Lys414Glu variant may impact protein binding and activity (PMID: 21831042, 8325892, 10525657). However, these types of assays may not accurately represent biological function. Animal models in mice have shown that this variant causes Monogenic Diabetes (PMID: 17353190). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3 (Richards 2015).

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

Last Updated: Oct 30, 2021

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