NM_000162.5(GCK):c.539A>G (p.Asn180Ser) AND not provided

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 1, 2024
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:: RCV003555339.1

Allele description [Variation Report for NM_000162.5(GCK):c.539A>G (p.Asn180Ser)]

NM_000162.5(GCK):c.539A>G (p.Asn180Ser)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.539A>G (p.Asn180Ser)

HGVS:

NC_000007.14:g.44150009T>C
NG_008847.2:g.53162A>G
NM_000162.5:c.539A>GMANE SELECT
NM_001354800.1:c.539A>G
NM_033507.3:c.542A>G
NM_033508.3:c.536A>G
NP_000153.1:p.Asn180Ser
NP_001341729.1:p.Asn180Ser
NP_277042.1:p.Asn181Ser
NP_277043.1:p.Asn179Ser
LRG_1074t1:c.539A>G
LRG_1074t2:c.542A>G
LRG_1074:g.53162A>G
LRG_1074p1:p.Asn180Ser
LRG_1074p2:p.Asn181Ser
NC_000007.13:g.44189608T>C

Protein change:

N179S

Molecular consequence:

NM_000162.5:c.539A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.539A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.542A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.536A>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
SCV004295175	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 1, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19790256, 24804978, 31063852, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004295175

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 1, 2024)

germline

clinical testing

PubMed (4)
[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

Molecular and clinical characterization of glucokinase maturity-onset diabetes of the young (GCK-MODY) in Japanese patients.

Kawakita R, Hosokawa Y, Fujimaru R, Tamagawa N, Urakami T, Takasawa K, Moriya K, Mizuno H, Maruo Y, Takuwa M, Nagasaka H, Nishi Y, Yamamoto Y, Aizu K, Yorifuji T.

Diabet Med. 2014 Nov;31(11):1357-62. doi: 10.1111/dme.12487. Epub 2014 May 24.

PubMed [citation]

PMID:: 24804978

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV004295175.1

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

Description

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 180 of the GCK protein (p.Asn180Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of maturity onset diabetes of the young (PMID: 19790256; Invitae). 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.Asn180 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 24804978, 31063852), which suggests that this may be a clinically significant amino acid residue. 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: Feb 20, 2024

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