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NM_000162.5(GCK):c.1268T>A (p.Phe423Tyr) AND Monogenic diabetes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 27, 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:
RCV004527301.1

Allele description [Variation Report for NM_000162.5(GCK):c.1268T>A (p.Phe423Tyr)]

NM_000162.5(GCK):c.1268T>A (p.Phe423Tyr)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1268T>A (p.Phe423Tyr)
Other names:
NM_000162.5(GCK):c.1268T>A
HGVS:
  • NC_000007.14:g.44145266A>T
  • NG_008847.2:g.57905T>A
  • NM_000162.5:c.1268T>AMANE SELECT
  • NM_001354800.1:c.1268T>A
  • NM_001354801.1:c.257T>A
  • NM_001354802.1:c.128T>A
  • NM_001354803.2:c.302T>A
  • NM_033507.3:c.1271T>A
  • NM_033508.3:c.1265T>A
  • NP_000153.1:p.Phe423Tyr
  • NP_001341729.1:p.Phe423Tyr
  • NP_001341730.1:p.Phe86Tyr
  • NP_001341731.1:p.Phe43Tyr
  • NP_001341732.1:p.Phe101Tyr
  • NP_277042.1:p.Phe424Tyr
  • NP_277043.1:p.Phe422Tyr
  • LRG_1074t1:c.1268T>A
  • LRG_1074t2:c.1271T>A
  • LRG_1074:g.57905T>A
  • LRG_1074p1:p.Phe423Tyr
  • LRG_1074p2:p.Phe424Tyr
  • NC_000007.13:g.44184865A>T
  • NM_000162.3:c.1268T>A
Protein change:
F101Y
Links:
dbSNP: rs193922273
NCBI 1000 Genomes Browser:
rs193922273
Molecular consequence:
  • NM_000162.5:c.1268T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1268T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.257T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354802.1:c.128T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.302T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1271T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1265T>A - 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
SCV005040671ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)		Pathogenic
(Apr 27, 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, SCV005040671.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1268T>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to tyrosine at codon 423 (p.(Phe423Tyr)) of NM_000162.5. 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.801, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in eight unrelated individuals with hyperglycemia (PS4; PMIDs: 23843579, 31968686, internal lab contributors). This variant segregated with hyperglycemia, with three informative meioses in two families (PP1_Moderate; PMIDs: 28012402, 23843579). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6% and OGTT with minimal increment <3 mmol/l) (PP4_Moderate; PMID: 23843579). In summary, c.1268T>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PP1_Moderate, PM2_supporting, PP2, PP3.

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

Last Updated: May 7, 2024