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NM_000162.5(GCK):c.676G>C (p.Val226Leu) AND Monogenic diabetes

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Feb 2, 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:
RCV003494029.2

Allele description [Variation Report for NM_000162.5(GCK):c.676G>C (p.Val226Leu)]

NM_000162.5(GCK):c.676G>C (p.Val226Leu)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.676G>C (p.Val226Leu)
Other names:
NM_033508.3:c.673G>C
HGVS:
  • NC_000007.14:g.44149763C>G
  • NG_008847.2:g.53408G>C
  • NM_000162.5:c.676G>CMANE SELECT
  • NM_001354800.1:c.676G>C
  • NM_033507.3:c.679G>C
  • NM_033508.3:c.673G>C
  • NP_000153.1:p.Val226Leu
  • NP_001341729.1:p.Val226Leu
  • NP_277042.1:p.Val227Leu
  • NP_277043.1:p.Val225Leu
  • LRG_1074t1:c.676G>C
  • LRG_1074t2:c.679G>C
  • LRG_1074:g.53408G>C
  • LRG_1074p1:p.Val226Leu
  • LRG_1074p2:p.Val227Leu
  • NC_000007.13:g.44189362C>G
Protein change:
V225L
Molecular consequence:
  • NM_000162.5:c.676G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.676G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.679G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.673G>C - 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
SCV004242360ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)		Uncertain significance
(Feb 2, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004242360.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.676G>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to leucine at codon 226 (p.(Val226leu)) of NM_000162.5. This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). 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 absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.676G>A p.Val226Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Val226Leu (PM5_Supporting). This variant has a REVEL score of 0.667 which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 21348868). In summary, c.676G>C meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PP2, PM2_Supporting, PM5_Supporting.

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

Last Updated: Jun 23, 2024