NM_000162.5(GCK):c.1358C>G (p.Ser453Trp) AND not provided

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 27, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003555319.2

Allele description [Variation Report for NM_000162.5(GCK):c.1358C>G (p.Ser453Trp)]

NM_000162.5(GCK):c.1358C>G (p.Ser453Trp)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1358C>G (p.Ser453Trp)

HGVS:

NC_000007.14:g.44145176G>C
NG_008847.2:g.57995C>G
NM_000162.5:c.1358C>GMANE SELECT
NM_001354800.1:c.1358C>G
NM_001354801.1:c.347C>G
NM_001354802.1:c.218C>G
NM_001354803.2:c.392C>G
NM_033507.3:c.1361C>G
NM_033508.3:c.1355C>G
NP_000153.1:p.Ser453Trp
NP_001341729.1:p.Ser453Trp
NP_001341730.1:p.Ser116Trp
NP_001341731.1:p.Ser73Trp
NP_001341732.1:p.Ser131Trp
NP_277042.1:p.Ser454Trp
NP_277043.1:p.Ser452Trp
LRG_1074t1:c.1358C>G
LRG_1074t2:c.1361C>G
LRG_1074:g.57995C>G
LRG_1074p1:p.Ser453Trp
LRG_1074p2:p.Ser454Trp
NC_000007.13:g.44184775G>C

Protein change:

S116W

Molecular consequence:

NM_000162.5:c.1358C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.1358C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354801.1:c.347C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354802.1:c.218C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354803.2:c.392C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.1361C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.1355C>G - 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
SCV004295118	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19790256, 14517956, 16731834, 18399931, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004295118

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 27, 2023)

germline

clinical testing

PubMed (5)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia.

Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S, Gloyn AL.

Hum Mutat. 2009 Nov;30(11):1512-26. doi: 10.1002/humu.21110. Review.

PubMed [citation]

PMID:: 19790256

Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY).

Thomson KL, Gloyn AL, Colclough K, Batten M, Allen LI, Beards F, Hattersley AT, Ellard S.

Hum Mutat. 2003 Nov;22(5):417.

PubMed [citation]

PMID:: 14517956

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004295118.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 453 of the GCK protein (p.Ser453Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (MODY) (PMID: 19790256). 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%. This variant disrupts the p.Ser453 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14517956, 16731834, 18399931; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Sep 29, 2024

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