NM_000162.5(GCK):c.1232C>T (p.Ser411Phe) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 29, 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:: RCV003060097.3

Allele description [Variation Report for NM_000162.5(GCK):c.1232C>T (p.Ser411Phe)]

NM_000162.5(GCK):c.1232C>T (p.Ser411Phe)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1232C>T (p.Ser411Phe)

HGVS:

NC_000007.14:g.44145518G>A
NG_008847.2:g.57653C>T
NM_000162.5:c.1232C>TMANE SELECT
NM_001354800.1:c.1232C>T
NM_001354801.1:c.221C>T
NM_001354802.1:c.92C>T
NM_001354803.2:c.266C>T
NM_033507.3:c.1235C>T
NM_033508.3:c.1229C>T
NP_000153.1:p.Ser411Phe
NP_001341729.1:p.Ser411Phe
NP_001341730.1:p.Ser74Phe
NP_001341731.1:p.Ser31Phe
NP_001341732.1:p.Ser89Phe
NP_277042.1:p.Ser412Phe
NP_277043.1:p.Ser410Phe
LRG_1074t1:c.1232C>T
LRG_1074t2:c.1235C>T
LRG_1074:g.57653C>T
LRG_1074p1:p.Ser411Phe
LRG_1074p2:p.Ser412Phe
NC_000007.13:g.44185117G>A

Protein change:

S31F

Molecular consequence:

NM_000162.5:c.1232C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.1232C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354801.1:c.221C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354802.1:c.92C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354803.2:c.266C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.1235C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.1229C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003439538	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 29, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12050210, 17573900, 24804978, 19790256, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003439538

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 29, 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

Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families.

Barrio R, Bellanné-Chantelot C, Moreno JC, Morel V, Calle H, Alonso M, Mustieles C.

J Clin Endocrinol Metab. 2002 Jun;87(6):2532-9.

PubMed [citation]

PMID:: 12050210

Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain.

Estalella I, Rica I, Perez de Nanclares G, Bilbao JR, Vazquez JA, San Pedro JI, Busturia MA, Castaño L; Spanish MODY Group.

Clin Endocrinol (Oxf). 2007 Oct;67(4):538-46. Epub 2007 Jun 15.

PubMed [citation]

PMID:: 17573900

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003439538.2

#	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 phenylalanine, which is neutral and non-polar, at codon 411 of the GCK protein (p.Ser411Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant maturity-onset diabetes of the young (PMID: 12050210, 17573900, 24804978). ClinVar contains an entry for this variant (Variation ID: 2136506). 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. Experimental studies have shown that this missense change affects GCK function (PMID: 19790256). 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: Dec 7, 2024

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