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NM_000162.5(GCK):c.1139A>C (p.His380Pro) AND Maturity-onset diabetes of the young type 2

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 17, 2023
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:
RCV003388013.1

Allele description [Variation Report for NM_000162.5(GCK):c.1139A>C (p.His380Pro)]

NM_000162.5(GCK):c.1139A>C (p.His380Pro)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1139A>C (p.His380Pro)
Other names:
NM_000162.5(GCK):c.1139A>C; p.His380Pro
HGVS:
  • NC_000007.14:g.44145611T>G
  • NG_008847.2:g.57560A>C
  • NM_000162.5:c.1139A>CMANE SELECT
  • NM_001354800.1:c.1139A>C
  • NM_001354801.1:c.128A>C
  • NM_001354802.1:c.-2A>C
  • NM_001354803.2:c.173A>C
  • NM_033507.3:c.1142A>C
  • NM_033508.3:c.1136A>C
  • NP_000153.1:p.His380Pro
  • NP_001341729.1:p.His380Pro
  • NP_001341730.1:p.His43Pro
  • NP_001341732.1:p.His58Pro
  • NP_277042.1:p.His381Pro
  • NP_277043.1:p.His379Pro
  • LRG_1074t1:c.1139A>C
  • LRG_1074t2:c.1142A>C
  • LRG_1074:g.57560A>C
  • LRG_1074p1:p.His380Pro
  • LRG_1074p2:p.His381Pro
  • NC_000007.13:g.44185210T>G
  • NM_000162.3:c.1139A>C
Protein change:
H379P
Links:
dbSNP: rs2128819280
NCBI 1000 Genomes Browser:
rs2128819280
Molecular consequence:
  • NM_001354802.1:c.-2A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000162.5:c.1139A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1139A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.128A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.173A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1142A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1136A>C - 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
SCV001623363Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Sep 17, 2023) 		germlineclinical testing

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

Citation Link

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Summary from all submissions

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

Citations

PubMed

Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia.

Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S, Gloyn AL.

Hum Mutat. 2009 Nov;30(11):1512-26. doi: 10.1002/humu.21110. Review.

PubMed [citation]
PMID:
19790256

A Comprehensive Analysis of Hungarian MODY Patients-Part II: Glucokinase MODY Is the Most Prevalent Subtype Responsible for about 70% of Confirmed Cases.

Gaál Z, Szűcs Z, Kántor I, Luczay A, Tóth-Heyn P, Benn O, Felszeghy E, Karádi Z, Madar L, Balogh I.

Life (Basel). 2021 Jul 30;11(8). doi:pii: 771. 10.3390/life11080771.

PubMed [citation]
PMID:
34440516
PMCID:
PMC8400228

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623363.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: GCK c.1139A>C (p.His380Pro) results in a non-conservative amino acid change located in the C-terminal domain (IPR022673) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Other variants affecting the same amino acid are listed in affected individuals: c.1138C>G (p.His380Asp), c.1140C>A (p.His380Gln) and c.1140C>G (p.His380Gln) are listed in association with MODY in the HGMD database providing supporting evidence for a critical relevance of this residue to GCK function. The variant was absent in 235200 control chromosomes in gnomAD. c.1139A>C has been reported in the literature in several individuals fulfilling the clinical and diagnostic criteria for GCK Hyperglycemia/Maturity Onset Diabetes of The Young 2 (example: Gaal_2021, Osbak_ 2009) and further corroborated by the MODY expert panel-2023 (unpublished personal correspondence). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34440516, 19790256). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. 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: Aug 25, 2024