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NM_000162.5(GCK):c.1136C>A (p.Ala379Glu) AND Maturity onset diabetes mellitus in young

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jul 23, 2020
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:
RCV002444444.9

Allele description [Variation Report for NM_000162.5(GCK):c.1136C>A (p.Ala379Glu)]

NM_000162.5(GCK):c.1136C>A (p.Ala379Glu)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1136C>A (p.Ala379Glu)
Other names:
NM_000162.5(GCK):c.1136C>A
HGVS:
  • NC_000007.14:g.44145614G>T
  • NG_008847.2:g.57557C>A
  • NM_000162.5:c.1136C>AMANE SELECT
  • NM_001354800.1:c.1136C>A
  • NM_001354801.1:c.125C>A
  • NM_001354802.1:c.-5C>A
  • NM_001354803.2:c.170C>A
  • NM_033507.3:c.1139C>A
  • NM_033508.3:c.1133C>A
  • NP_000153.1:p.Ala379Glu
  • NP_001341729.1:p.Ala379Glu
  • NP_001341730.1:p.Ala42Glu
  • NP_001341732.1:p.Ala57Glu
  • NP_277042.1:p.Ala380Glu
  • NP_277043.1:p.Ala378Glu
  • LRG_1074t1:c.1136C>A
  • LRG_1074t2:c.1139C>A
  • LRG_1074:g.57557C>A
  • LRG_1074p1:p.Ala379Glu
  • LRG_1074p2:p.Ala380Glu
  • NC_000007.13:g.44185213G>T
  • NM_000162.3:c.1136C>A
  • p.ALA379GLU
Protein change:
A378E
Links:
dbSNP: rs193922265
NCBI 1000 Genomes Browser:
rs193922265
Molecular consequence:
  • NM_001354802.1:c.-5C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000162.5:c.1136C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1136C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.125C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.170C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1139C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1133C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Maturity onset diabetes mellitus in young (MODY)
Synonyms:
Mason type diabetes
Identifiers:
MONDO: MONDO:0018911; MedGen: C0342276; Orphanet: 552; OMIM: 606391; Human Phenotype Ontology: HP:0004904

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002611504Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Jul 23, 2020) 		germlineclinical testing

PubMed (6)
[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

Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype.

Miller SP, Anand GR, Karschnia EJ, Bell GI, LaPorte DC, Lange AJ.

Diabetes. 1999 Aug;48(8):1645-51.

PubMed [citation]
PMID:
10426385

Biochemical characterization of novel glucokinase mutations isolated from Spanish maturity-onset diabetes of the young (MODY2) patients.

Estalella I, Garcia-Gimeno MA, Marina A, Castaño L, Sanz P.

J Hum Genet. 2008;53(5):460-466. doi: 10.1007/s10038-008-0271-5. Epub 2008 Mar 6.

PubMed [citation]
PMID:
18322640
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002611504.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The p.A379E variant (also known as c.1136C>A), located in coding exon 9 of the GCK gene, results from a C to A substitution at nucleotide position 1136. The alanine at codon 379 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration was confirmed in trans with a second disease-causing allele in a patient with neonatal diabetes mellitus (Wang Z et al. J Diabetes Investig, 2019 Jul;10:963-971). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Functional analysis revealed that A379E results in decreased enzyme activity as compared to wild-type (Wang Z et al. J Diabetes Investig, 2019 Jul;10:963-971). Based on internal structural analysis, A379E is more destabilizing to the structure of the hexokinase domain of GCK than several pathogenic variants within 20 Å and in the same domain (Petit P et al. Acta Crystallogr. D Biol. Crystallogr., 2011 Nov;67:929-35; Estalella I et al. J. Hum. Genet., 2008 Mar;53:460-466; Miller SP et al. Diabetes, 1999 Aug;48:1645-51; Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26). Another alteration at the same codon, p.A379V (c.1136C>T), has been described (Estalella I et al. J. Hum. Genet., 2008 Mar;53:460-466; Weinert LS et al. Diabetes Res. Clin. Pract., 2014 Nov;106:e44-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Sep 16, 2024