NM_000162.5(GCK):c.1130G>A (p.Arg377His) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Nov 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001818186.4

Allele description [Variation Report for NM_000162.5(GCK):c.1130G>A (p.Arg377His)]

NM_000162.5(GCK):c.1130G>A (p.Arg377His)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1130G>A (p.Arg377His)

Other names:

NM_000162.5(GCK):c.1130G>A

HGVS:

NC_000007.14:g.44145620C>T
NG_008847.2:g.57551G>A
NM_000162.5:c.1130G>AMANE SELECT
NM_001354800.1:c.1130G>A
NM_001354801.1:c.119G>A
NM_001354802.1:c.-11G>A
NM_001354803.2:c.164G>A
NM_033507.3:c.1133G>A
NM_033508.3:c.1127G>A
NP_000153.1:p.Arg377His
NP_001341729.1:p.Arg377His
NP_001341730.1:p.Arg40His
NP_001341732.1:p.Arg55His
NP_277042.1:p.Arg378His
NP_277043.1:p.Arg376His
LRG_1074t1:c.1130G>A
LRG_1074t2:c.1133G>A
LRG_1074:g.57551G>A
LRG_1074p1:p.Arg377His
LRG_1074p2:p.Arg378His
NC_000007.13:g.44185219C>T
NC_000007.13:g.44185219C>T
NM_000162.3:c.1130G>A
p.ARG377HIS

Protein change:

R376H

Links:

dbSNP: rs193922264

NCBI 1000 Genomes Browser:

rs193922264

Molecular consequence:

NM_001354802.1:c.-11G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000162.5:c.1130G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.1130G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354801.1:c.119G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354803.2:c.164G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.1133G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.1127G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002064158	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Jan 17, 2022)	germline	clinical testing	Citation Link,
SCV004295141	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 17, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24430320, 30155490, 17573900, 19790256, 34746319, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002064158

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Jan 17, 2022)

germline

clinical testing

Citation Link,

SCV004295141

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 17, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia.

Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT.

JAMA. 2014 Jan 15;311(3):279-86. doi: 10.1001/jama.2013.283980.

PubMed [citation]

PMID:: 24430320

Lower Circulating miR-122 Level in Patients with HNF1A Variant-Induced Diabetes Compared with Type 2 Diabetes.

Huang X, Gong S, Ma Y, Cai X, Zhou L, Luo Y, Li M, Liu W, Zhang S, Zhang X, Ren Q, Zhu Y, Zhou X, Zhang R, Chen L, Gao X, Zhang F, Wang Y, Han X, Ji L.

J Diabetes Res. 2018;2018:7842064. doi: 10.1155/2018/7842064.

PubMed [citation]

PMID:: 30155490
PMCID:: PMC6093029

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV002064158.2

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

Description

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 30155490, 24430320, 17573900, 34746319)

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

From Invitae, SCV004295141.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 377 of the GCK protein (p.Arg377His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant maturity-onset diabetes of the young and/or GCK-related conditions and/or GCK-related conditions (PMID: 17573900, 24430320, 30155490, 34746319). ClinVar contains an entry for this variant (Variation ID: 36176). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCK protein function with a positive predictive value of 80%. This variant disrupts the p.Arg377 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 17573900, 19790256, 34746319), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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 7, 2024

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