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NM_000162.5(GCK):c.679+2T>C AND Monogenic diabetes

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Feb 4, 2025
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:
RCV005238539.1

Allele description [Variation Report for NM_000162.5(GCK):c.679+2T>C]

NM_000162.5(GCK):c.679+2T>C

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.679+2T>C
HGVS:
  • NC_000007.14:g.44149758A>G
  • NG_008847.2:g.53413T>C
  • NM_000162.5:c.679+2T>CMANE SELECT
  • NM_001354800.1:c.679+2T>C
  • NM_033507.3:c.682+2T>C
  • NM_033508.3:c.676+2T>C
  • LRG_1074t1:c.679+2T>C
  • LRG_1074t2:c.682+2T>C
  • LRG_1074:g.53413T>C
  • NC_000007.13:g.44189357A>G
Molecular consequence:
  • NM_000162.5:c.679+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354800.1:c.679+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_033507.3:c.682+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_033508.3:c.676+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Monogenic diabetes
Identifiers:
MONDO: MONDO:0015967; MedGen: C3888631

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005886648Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely pathogenic
(Feb 4, 2025) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.

Mirshahi UL, Colclough K, Wright CF, Wood AR, Beaumont RN, Tyrrell J, Laver TW, Stahl R, Golden A, Goehringer JM; Geisinger-Regeneron DiscovEHR Collaboration, Frayling TF, Hattersley AT, Carey DJ, Weedon MN, Patel KA.

Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. doi: 10.1016/j.ajhg.2022.09.014. Epub 2022 Oct 17.

PubMed [citation]
PMID:
36257325
PMCID:
PMC9674944

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005886648.1

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

Description

Variant summary: GCK c.679+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of GCK function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251402 control chromosomes. c.679+2T>C has been reported in the literature in individuals affected with Monogenic Diabetes (example: Mirshahi_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36257325). No submitters have cited clinical-significance assessments for this variant to ClinVar. 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: Mar 22, 2025