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NM_000162.5(GCK):c.1142T>C (p.Met381Thr) AND Monogenic diabetes

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 17, 2023
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:
RCV003318528.1

Allele description [Variation Report for NM_000162.5(GCK):c.1142T>C (p.Met381Thr)]

NM_000162.5(GCK):c.1142T>C (p.Met381Thr)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.1142T>C (p.Met381Thr)
Other names:
NM_001354803.2:c.176T>C
HGVS:
  • NC_000007.14:g.44145608A>G
  • NG_008847.2:g.57563T>C
  • NM_000162.5:c.1142T>CMANE SELECT
  • NM_001354800.1:c.1142T>C
  • NM_001354801.1:c.131T>C
  • NM_001354802.1:c.2T>C
  • NM_001354803.2:c.176T>C
  • NM_033507.3:c.1145T>C
  • NM_033508.3:c.1139T>C
  • NP_000153.1:p.Met381Thr
  • NP_001341729.1:p.Met381Thr
  • NP_001341730.1:p.Met44Thr
  • NP_001341731.1:p.Met1Thr
  • NP_001341732.1:p.Met59Thr
  • NP_277042.1:p.Met382Thr
  • NP_277043.1:p.Met380Thr
  • LRG_1074t1:c.1142T>C
  • LRG_1074t2:c.1145T>C
  • LRG_1074:g.57563T>C
  • LRG_1074p1:p.Met381Thr
  • LRG_1074p2:p.Met382Thr
  • NC_000007.13:g.44185207A>G
Protein change:
M1T
Molecular consequence:
  • NM_001354802.1:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_000162.5:c.1142T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.1142T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354801.1:c.131T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354802.1:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354803.2:c.176T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.1145T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.1139T>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
SCV004022351ClinGen Monogenic Diabetes Variant Curation Expert Panel
reviewed by expert panel

(ClinGen Diabetes ACMG Specifications GCK V1.2.0)		Pathogenic
(Jul 17, 2023) 		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, SCV004022351.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.1142T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to threonine at codon 381 (p.(Met381Thr)) 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 0.93, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 30257192). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 18 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 30257192, internal lab contributors). At least 5 of these individuals have a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Additionally, this variant segregated with diabetes, with at least 16 informative meioses in 6 families with MODY (PP1_Strong; PMID 30257192, internal lab contributors). In summary, the c.1142T>C variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PP4_Moderate, PS4, PP2, PP3, PM2_Supporting.

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

Last Updated: Sep 3, 2023