NM_000162.5(GCK):c.1222G>A (p.Val408Met) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 21, 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:: RCV001733092.5

Allele description [Variation Report for NM_000162.5(GCK):c.1222G>A (p.Val408Met)]

NM_000162.5(GCK):c.1222G>A (p.Val408Met)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1222G>A (p.Val408Met)

HGVS:

NC_000007.14:g.44145528C>T
NG_008847.2:g.57643G>A
NM_000162.5:c.1222G>AMANE SELECT
NM_001354800.1:c.1222G>A
NM_001354801.1:c.211G>A
NM_001354802.1:c.82G>A
NM_001354803.2:c.256G>A
NM_033507.3:c.1225G>A
NM_033508.3:c.1219G>A
NP_000153.1:p.Val408Met
NP_001341729.1:p.Val408Met
NP_001341730.1:p.Val71Met
NP_001341731.1:p.Val28Met
NP_001341732.1:p.Val86Met
NP_277042.1:p.Val409Met
NP_277043.1:p.Val407Met
LRG_1074t1:c.1222G>A
LRG_1074t2:c.1225G>A
LRG_1074:g.57643G>A
LRG_1074p1:p.Val408Met
LRG_1074p2:p.Val409Met
NC_000007.13:g.44185127C>T
NM_000162.3:c.1222G>A

Protein change:

V28M

Links:

dbSNP: rs1293307672

NCBI 1000 Genomes Browser:

rs1293307672

Molecular consequence:

NM_000162.5:c.1222G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.1222G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354801.1:c.211G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354802.1:c.82G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354803.2:c.256G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.1219G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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MAG: 30S ribosomal protein S1 [Candidatus Beckwithbacteria bacterium GW2011_GWC1...
MAG: 30S ribosomal protein S1 [Candidatus Beckwithbacteria bacterium GW2011_GWC1_49_16]
gi|837349766|gnl|BanfieldUCB|UY43_C 0202|gb|AKM78950.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001983264	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Sep 28, 2021)	germline	clinical testing	Citation Link,
SCV003439925	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 21, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 29056535, 33565752, 34686905, 34697762, 28323911, 30663027, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001983264

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Sep 28, 2021)

germline

clinical testing

Citation Link,

SCV003439925

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 21, 2023)

germline

clinical testing

PubMed (7)
[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

Analysis of the GCK gene in 79 MODY type 2 patients: A multicenter Turkish study, mutation profile and description of twenty novel mutations.

Aykut A, Karaca E, Onay H, Gökşen D, Çetinkalp Ş, Eren E, Ersoy B, Çakır EP, Büyükinan M, Kara C, Anık A, Kırel B, Özen S, Atik T, Darcan Ş, Özkınay F.

Gene. 2018 Jan 30;641:186-189. doi: 10.1016/j.gene.2017.10.057. Epub 2017 Oct 19.

PubMed [citation]

PMID:: 29056535

The Application of Next Generation Sequencing Maturity Onset Diabetes of the Young Gene Panel in Turkish Patients from Trakya Region

Yalçıntepe S, Özgüç Çömlek F, Gürkan H, Demir S, Atlı Eİ, Atlı E, Eker D, Tütüncüler Kökenli F.

J Clin Res Pediatr Endocrinol. 2021 Aug 23;13(3):320-331. doi: 10.4274/jcrpe.galenos.2021.2020.0285. Epub 2021 Feb 10.

PubMed [citation]

PMID:: 33565752
PMCID:: PMC8388052

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV001983264.2

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

Description

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 28323911, 30663027)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003439925.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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. This variant disrupts the p.Val408 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29056535, 33565752, 34686905, 34697762). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1300949). This missense change has been observed in individual(s) with diabetes mellitus and/or maturity onset diabetes of the young (PMID: 28323911, 30663027). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 408 of the GCK protein (p.Val408Met).

#	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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