NM_000162.5(GCK):c.127C>T (p.Arg43Cys) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 12, 2024
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:: RCV000711761.7

Allele description [Variation Report for NM_000162.5(GCK):c.127C>T (p.Arg43Cys)]

NM_000162.5(GCK):c.127C>T (p.Arg43Cys)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.127C>T (p.Arg43Cys)

Other names:

NM_000162.5(GCK):c.127C>T; p.Arg43Cys

HGVS:

NC_000007.14:g.44153382G>A
NG_008847.2:g.49789C>T
NM_000162.5:c.127C>TMANE SELECT
NM_001354800.1:c.127C>T
NM_033507.3:c.130C>T
NM_033508.3:c.124C>T
NP_000153.1:p.Arg43Cys
NP_001341729.1:p.Arg43Cys
NP_277042.1:p.Arg44Cys
NP_277043.1:p.Arg42Cys
LRG_1074t1:c.127C>T
LRG_1074t2:c.130C>T
LRG_1074:g.49789C>T
LRG_1074p1:p.Arg43Cys
LRG_1074p2:p.Arg44Cys
NC_000007.13:g.44192981G>A
NC_000007.13:g.44192981G>A
NM_000162.3:c.127C>T

Protein change:

R42C

Links:

dbSNP: rs1486280029

NCBI 1000 Genomes Browser:

rs1486280029

Molecular consequence:

NM_000162.5:c.127C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.127C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.130C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.124C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Posterior Myocardial Ischemia (Archived) - StatPearls
Posterior Myocardial Ischemia (Archived) - StatPearls

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000842155	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (May 11, 2020)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 30592380, 19790256, 21348868, 23771172, 25015100, 24549415, 21521320, 26467025
SCV004295191	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 19790256, 30592380, 11942313, 22493702, 22611063, 28726111, 30155490, 30245511, 31638168, 33046911, 34108472, 28492532
SCV004565214	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Jul 13, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000842155

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(May 11, 2020)

unknown

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV004295191

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 12, 2024)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV004565214

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Pathogenic
(Jul 13, 2023)

germline

clinical testing

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel glucokinase mutations in patients with monogenic diabetes - clinical outline of GCK-MD and potential for founder effect in Slavic population.

Borowiec M, Antosik K, Fendler W, Deja G, Jarosz-Chobot P, Mysliwiec M, Zmyslowska A, Malecki M, Szadkowska A, Mlynarski W.

Clin Genet. 2012 Mar;81(3):278-83. doi: 10.1111/j.1399-0004.2011.01656.x. Epub 2011 Mar 18.

PubMed [citation]

PMID:: 21348868

Improved genetic testing for monogenic diabetes using targeted next-generation sequencing.

Ellard S, Lango Allen H, De Franco E, Flanagan SE, Hysenaj G, Colclough K, Houghton JA, Shepherd M, Hattersley AT, Weedon MN, Caswell R.

Diabetologia. 2013 Sep;56(9):1958-63. doi: 10.1007/s00125-013-2962-5. Epub 2013 Jun 15.

PubMed [citation]

PMID:: 23771172
PMCID:: PMC3737433

See all PubMed Citations (18)

Details of each submission

From Athena Diagnostics, SCV000842155.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Found in multiple individuals with expected phenotype for this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected individuals from a single family.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004295191.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 43 of the GCK protein (p.Arg43Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 19790256, 30592380). ClinVar contains an entry for this variant (Variation ID: 585911). 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 not expected to disrupt GCK protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 30592380). This variant disrupts the p.Arg43 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11942313, 22493702, 22611063, 28726111, 30155490, 30245511, 31638168, 33046911, 34108472; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as 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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004565214.1

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

Description

The GCK c c.127C>T; p.Arg43Cys variant (rs1486280029) is reported in the literature in multiple individuals and families affected with MODY and neonatal diabetes (Ellard 2013, Marucci 2023, Osbak 2009, Wang 2019). This variant is also reported in ClinVar (Variation ID: 585911). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Gly, Ser, His, Pro) have been reported in individuals with MODY with most of them demonstrating pathogenicity (Osbak 2009). Computational analyses predict that this variant is neutral (REVEL: 0.924). Based on available information, this variant is considered to be pathogenic. References: Ellard S et al. Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia. 2013 Sep;56(9):1958-63. PMID: 23771172. Marucci A et al. MODY patients carrying mutation in syndromic diabetes genes. An Italian single-center experience. Acta Diabetol. 2023 Jan;60(1):131-135. PMID: 36227502. Osbak KK et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009 Nov;30(11):1512-26. PMID: 19790256. Wang Z et al. Identification and functional analysis of GCK gene mutations in 12 Chinese families with hyperglycemia. J Diabetes Investig. 2019 Jul;10(4):963-971. PMID: 30592380.

#	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: Oct 13, 2024

ClinVar

Relating variation to medicine