NM_000162.5(GCK):c.1270C>T (p.His424Tyr) AND Monogenic diabetes

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Nov 23, 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:: RCV003445164.2

Allele description [Variation Report for NM_000162.5(GCK):c.1270C>T (p.His424Tyr)]

NM_000162.5(GCK):c.1270C>T (p.His424Tyr)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1270C>T (p.His424Tyr)

Other names:

NM_000162.5(GCK):c.1270C>T; p.His424Tyr

HGVS:

NC_000007.14:g.44145264G>A
NG_008847.2:g.57907C>T
NM_000162.5:c.1270C>TMANE SELECT
NM_001354800.1:c.1270C>T
NM_001354801.1:c.259C>T
NM_001354802.1:c.130C>T
NM_001354803.2:c.304C>T
NM_033507.3:c.1273C>T
NM_033508.3:c.1267C>T
NP_000153.1:p.His424Tyr
NP_001341729.1:p.His424Tyr
NP_001341730.1:p.His87Tyr
NP_001341731.1:p.His44Tyr
NP_001341732.1:p.His102Tyr
NP_277042.1:p.His425Tyr
NP_277043.1:p.His423Tyr
LRG_1074t1:c.1270C>T
LRG_1074t2:c.1273C>T
LRG_1074:g.57907C>T
LRG_1074p1:p.His424Tyr
LRG_1074p2:p.His425Tyr
NC_000007.13:g.44184863G>A
NM_000162.3:c.1270C>T

Protein change:

H102Y

Molecular consequence:

NM_000162.5:c.1270C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.1270C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354801.1:c.259C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354802.1:c.130C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354803.2:c.304C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.1273C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.1267C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Monogenic diabetes
Identifiers:: MONDO: MONDO:0015967; MedGen: C3888631

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004174251	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)	Likely pathogenic (Nov 23, 2023)	germline	curation	Citation Link,
SCV004223410	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 7, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19410318, 28726111, 35472491, 22035297 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004174251

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0)

Likely pathogenic
(Nov 23, 2023)

germline

curation

Citation Link,

SCV004223410

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Nov 7, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Identification of eight new mutations in the GCK gene by DHPLC screening in a Spanish population.

Solera J, Arias P, Amiñoso C, González-Casado I, Garre P, Herranz L, Villarroel A, Cruz M, Jáñez M, Pallardo LF, Gracia R.

Diabetes Res Clin Pract. 2009 Jul;85(1):20-3. doi: 10.1016/j.diabres.2009.04.002. Epub 2009 May 1.

PubMed [citation]

PMID:: 19410318

Glucokinase mutations in pediatric patients with impaired fasting glucose.

Aloi C, Salina A, Minuto N, Tallone R, Lugani F, Mascagni A, Mazza O, Cassanello M, Maghnie M, d'Annunzio G.

Acta Diabetol. 2017 Oct;54(10):913-923. doi: 10.1007/s00592-017-1021-y. Epub 2017 Jul 19.

PubMed [citation]

PMID:: 28726111

See all PubMed Citations (4)

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV004174251.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.1270C>T variant in the glucokinase gene, GCK, causes an amino acid change of histidine to tyrosine at codon 424 (p.(His424Tyr)) 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 0.897, 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 6 unrelated individuals with hyperglycemia (PS4_Moderate; ClinVar: 1709730, PMIDs: 27726111, 22035297, 31595705 internal lab contributors), including 3 individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% as well as OGTT increment < 3 mmol/L and/or negative antibodies in untreated pediatric case) (PP4_Moderate; PMIDs: 19410318, 28726111, internal lab contributors). This variant segregated with hyperglycemia, with 4 informative meioses in 1 family (PP1_Moderate; PMIDs: 22035297). In summary, c.1270C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PP1_Moderate, PP4_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004223410.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: GCK c.1270C>T (p.His424Tyr) results in a conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 244634 control chromosomes. c.1270C>T has been reported in the literature in individuals affected with clinical features of GCK-associated Monogenic Diabetes (example, Soldera_2009, Borowiec_2012, Aloi_2017, Campos Franco_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28726111, 22035297, 35472491, 19410318). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 19, 2024

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