NM_000162.5(GCK):c.605T>C (p.Met202Thr) AND not specified

Clinical significance:Uncertain significance (Last evaluated: Jan 30, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000029896.3

Allele description [Variation Report for NM_000162.5(GCK):c.605T>C (p.Met202Thr)]

NM_000162.5(GCK):c.605T>C (p.Met202Thr)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.605T>C (p.Met202Thr)
HGVS:
  • NC_000007.14:g.44149834A>G
  • NG_008847.2:g.53337T>C
  • NM_000162.5:c.605T>CMANE SELECT
  • NM_001354800.1:c.605T>C
  • NM_033507.3:c.608T>C
  • NM_033508.3:c.602T>C
  • NP_000153.1:p.Met202Thr
  • NP_001341729.1:p.Met202Thr
  • NP_277042.1:p.Met203Thr
  • NP_277043.1:p.Met201Thr
  • LRG_1074t1:c.605T>C
  • LRG_1074t2:c.608T>C
  • LRG_1074:g.53337T>C
  • LRG_1074p1:p.Met202Thr
  • LRG_1074p2:p.Met203Thr
  • NC_000007.13:g.44189433A>G
  • NM_000162.3:c.605T>C
Protein change:
M201T
Links:
dbSNP: rs193922311
NCBI 1000 Genomes Browser:
rs193922311
Molecular consequence:
  • NM_000162.5:c.605T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.605T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.608T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.602T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000052551Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Jan 30, 2019)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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, CastaƱo L; Spanish MODY Group..

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

PubMed [citation]
PMID:
17573900

Characteristics of maturity onset diabetes of the young in a large diabetes center.

Chambers C, Fouts A, Dong F, Colclough K, Wang Z, Batish SD, Jaremko M, Ellard S, Hattersley AT, Klingensmith G, Steck AK.

Pediatr Diabetes. 2016 Aug;17(5):360-7. doi: 10.1111/pedi.12289. Epub 2015 Jun 8.

PubMed [citation]
PMID:
26059258
PMCID:
PMC4934136
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052551.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: The variant, GCK c.605T>C (p.Met202Thr) results in a non-conservative amino acid change located in the Hexokinase, N-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function consistent with an ExAC z score of 4.39 indicative of a gene relatively intolerant to benign missense variation (ACMG PP3, PP2). The variant allele was found at a frequency of 8.1e-06 in 246536 control chromosomes (gnomAD). The variant, c.605T>C has been reported in the literature in individuals affected with Maturity Onset Diabetes of the Young 2 (Chambers_2016, Estalella_2007, Gozalan_2012). In one of these reports, this variant was reported as a de-novo occurrence however the data provided does not confirm this finding (Gozalan_2012; ACMG PM6). Furthermore, one of these reports reflects a conflicting classification of this variant relative to its latest ClinVar submission by the same testing laboratory (Chambers_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and has classified the variant as uncertain significance. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. As summarized above, at-least three new reports indicating its presence in individuals diagnosed with MODY2 or a related diabetic phenotype have emerged since its original classification. Based on the evidence outlined above, until additional functional impact and unequivocal co-segregation with disease in additional families/individuals with MODY2 is obtained the variant was classified as VUS Possibly Pathogenic.

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

Last Updated: Jun 14, 2021

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