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NM_000162.5(GCK):c.1160C>T (p.Ala387Val) AND Monogenic diabetes

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Feb 28, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV001248970.4

Allele description [Variation Report for NM_000162.5(GCK):c.1160C>T (p.Ala387Val)]

NM_000162.5(GCK):c.1160C>T (p.Ala387Val)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1160C>T (p.Ala387Val)
Other names:
NM_000162.5(GCK):c.1160C>T
HGVS:
  • NC_000007.14:g.44145590G>A
  • NG_008847.2:g.57581C>T
  • NM_000162.3(GCK):c.1160C>T
  • NM_000162.5:c.1160C>TMANE SELECT
  • NM_001354800.1:c.1160C>T
  • NM_001354801.1:c.149C>T
  • NM_001354802.1:c.20C>T
  • NM_001354803.2:c.194C>T
  • NM_033507.3:c.1163C>T
  • NM_033508.3:c.1157C>T
  • NP_000153.1:p.Ala387Val
  • NP_001341729.1:p.Ala387Val
  • NP_001341730.1:p.Ala50Val
  • NP_001341731.1:p.Ala7Val
  • NP_001341732.1:p.Ala65Val
  • NP_277042.1:p.Ala388Val
  • NP_277043.1:p.Ala386Val
  • LRG_1074t1:c.1160C>T
  • LRG_1074t2:c.1163C>T
  • LRG_1074:g.57581C>T
  • LRG_1074p1:p.Ala387Val
  • LRG_1074p2:p.Ala388Val
  • NC_000007.13:g.44185189G>A
  • NC_000007.13:g.44185189G>A
  • NM_000162.3(GCK):c.1160C>T
  • NM_000162.3:c.1160C>T
Protein change:
A386V
Links:
dbSNP: rs193921338
NCBI 1000 Genomes Browser:
rs193921338
Molecular consequence:
  • NM_000162.5:c.1160C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1160C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.149C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354802.1:c.20C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.194C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1163C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1157C>T - 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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001422802Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jan 22, 2020) 		germlinecuration

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

Citation Link,

SCV004697905ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)		Pathogenic
(Feb 28, 2024) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY).

Thomson KL, Gloyn AL, Colclough K, Batten M, Allen LI, Beards F, Hattersley AT, Ellard S.

Hum Mutat. 2003 Nov;22(5):417.

PubMed [citation]
PMID:
14517956

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
See all PubMed Citations (4)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422802.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (4)

Description

The p.Ala387Val variant in GCK has been reported in at least 4 individuals (including 1 Czech individual, 1 Asian individual, and 1 Caucasian individual from the UK) with Monogenic Diabetes (PMID: 14517956, 19790256, 20337973), and has been identified in 0.003400% (1/29414) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193921338). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for a disease with clinical variability/reduced penetrance. 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: 36182). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Ala387Val have been reported in association with disease in ClinVar, suggesting that this variant is in an important functional domain and slightly supports pathogenicity (Variation ID: 435300, 36180, 36179). Two additional variants (p.Ala387Glu and p.Ala387Thr) causing a different amino acid change at the same position have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 19790256; Variation ID: 36181). The number of missense variants reported in GCK in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5, PM2_Supporting, PP2, PP3, PS4_Supporting, PM1_Supporting (Richards 2015).

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

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004697905.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1160C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 387 (p. (Ala387Val)) of NM_000162.5. This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to no copies in the European non-Finnish subpopulation and one copy in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is located in the larger hexokinase domain of the GCK gene (PMID: 31638168) but this variant does not reside in an amino acid that directly binds glucose or ATP, which is defined as critical for the protein's function by the ClinGen MDEP, so it does not meet PM1. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.871 which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1159G>A p.(Ala387Thr) has been interpreted as pathogenic by the ClinGen MDEP, and p.Ala387Glu has a greater Grantham distance (PM5). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 34421822, Internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 34421822). This variant segregated with hyperglycemia, with five informative meioses in three families (PP1_Strong; PMID: 34421822, Internal lab contributor). In summary, c.1160C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (VCEP specifications version v1.3.0; approved 8/11/2023): PP2, PP3, PM2_Supporting, PP1_Strong, PM5, PS4_Moderate, PP4_Moderate.

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

Last Updated: Mar 30, 2024