NM_000162.5(GCK):c.562G>A (p.Ala188Thr) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 6, 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:: RCV000992055.11

Allele description [Variation Report for NM_000162.5(GCK):c.562G>A (p.Ala188Thr)]

NM_000162.5(GCK):c.562G>A (p.Ala188Thr)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.562G>A (p.Ala188Thr)

HGVS:

NC_000007.14:g.44149986C>T
NG_008847.2:g.53185G>A
NM_000162.5:c.562G>AMANE SELECT
NM_001354800.1:c.562G>A
NM_033507.3:c.565G>A
NM_033508.3:c.559G>A
NP_000153.1:p.Ala188Thr
NP_001341729.1:p.Ala188Thr
NP_277042.1:p.Ala189Thr
NP_277043.1:p.Ala187Thr
LRG_1074t1:c.562G>A
LRG_1074t2:c.565G>A
LRG_1074:g.53185G>A
LRG_1074p1:p.Ala188Thr
LRG_1074p2:p.Ala189Thr
NC_000007.13:g.44189585C>T
NC_000007.13:g.44189585C>T
NM_000162.3:c.562G>A

Protein change:

A187T

Links:

dbSNP: rs751279776

NCBI 1000 Genomes Browser:

rs751279776

Molecular consequence:

NM_000162.5:c.562G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.562G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.565G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.559G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PAPSS1 3'-phosphoadenosine 5'-phosphosulfate synthase 1 [Sus scrofa]
PAPSS1 3'-phosphoadenosine 5'-phosphosulfate synthase 1 [Sus scrofa]
Gene ID:106504748

Gene
Adenoidectomy
Adenoidectomy
Excision of the adenoids. (Dorland, 28th ed)<br/>

MeSH
Skin Diseases, Papulosquamous
Skin Diseases, Papulosquamous
A group of dermatoses with distinct morphologic features. The primary lesion is most commonly a papule, usually erythematous, with a variable degree of scaling on the surface....<br/>Year introduced: 1993

MeSH
Profile neighbors for GEO Profiles (Select 78877865) (200)
GEO Profiles
Chromosome neighbors for GEO Profiles (Select 78825548) (20)
GEO Profiles

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001144023	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Sep 6, 2023)	unknown	clinical testing	PubMed (18) [See all records that cite these PMIDs] 36257325, 36836406, 37101203, 35592779, 36504295, 24578721, 30257192, 20337973, 29207974, 28170077, 12955723, 16602010, 12050210, 14517956, 8314448, 8325892, 22761713, 26467025
SCV002067433	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 8, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003439965	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 25, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8325892, 8314448, 12050210, 28170077, 30257192, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001144023

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Sep 6, 2023)

unknown

clinical testing

PubMed (18)
[See all records that cite these PMIDs]

SCV002067433

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 8, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003439965

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 25, 2023)

germline

clinical testing

PubMed (6)
[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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.

Mirshahi UL, Colclough K, Wright CF, Wood AR, Beaumont RN, Tyrrell J, Laver TW, Stahl R, Golden A, Goehringer JM; Geisinger-Regeneron DiscovEHR Collaboration., Frayling TF, Hattersley AT, Carey DJ, Weedon MN, Patel KA.

Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. doi: 10.1016/j.ajhg.2022.09.014. Epub 2022 Oct 17.

PubMed [citation]

PMID:: 36257325
PMCID:: PMC9674944

The Mutation Spectrum of Rare Variants in the Gene of Adenosine Triphosphate (ATP)-Binding Cassette Subfamily C Member 8 in Patients with a MODY Phenotype in Western Siberia.

Ivanoshchuk D, Shakhtshneider E, Mikhailova S, Ovsyannikova A, Rymar O, Valeeva E, Orlov P, Voevoda M.

J Pers Med. 2023 Jan 19;13(2). doi:pii: 172. 10.3390/jpm13020172.

PubMed [citation]

PMID:: 36836406
PMCID:: PMC9967647

See all PubMed Citations (20)

Details of each submission

From Athena Diagnostics, SCV001144023.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with MODY in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 8325892, 30257192)

#	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 Genetic Services Laboratory, University of Chicago, SCV002067433.1

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

Description

This sequence change has been previously described in multiple patients and families with GCK-related MODY (PMID: 8314448, 30257192, 14517956, 29207974 and 20337973). This particular sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.00040% (dbSNP rs751279776). Experimental studies have indicated reduced enzymatic activity and protein stability for this sequence change (PMID: 30257192). The p.Ala188Thr change affects a highly conserved amino acid residue located in a Hexokinase domain of the GCK protein that is known to be functional. The p.Ala188Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These collective evidences indicate that this sequence change is pathogenic.

#	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 Invitae, SCV003439965.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 8325892, 30257192). 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: 804849). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 8314448, 12050210, 28170077, 30257192). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs751279776, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 188 of the GCK protein (p.Ala188Thr).

#	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: May 7, 2024

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