NM_000162.5(GCK):c.475A>G (p.Ile159Val) AND Cowden syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 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:: RCV004545258.1

Allele description [Variation Report for NM_000162.5(GCK):c.475A>G (p.Ile159Val)]

NM_000162.5(GCK):c.475A>G (p.Ile159Val)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.475A>G (p.Ile159Val)

HGVS:

NC_000007.14:g.44150964T>C
NG_008847.2:g.52207A>G
NM_000162.5:c.475A>GMANE SELECT
NM_001354800.1:c.475A>G
NM_033507.3:c.478A>G
NM_033508.3:c.472A>G
NP_000153.1:p.Ile159Val
NP_001341729.1:p.Ile159Val
NP_277042.1:p.Ile160Val
NP_277043.1:p.Ile158Val
LRG_1074t1:c.475A>G
LRG_1074t2:c.478A>G
LRG_1074:g.52207A>G
LRG_1074p1:p.Ile159Val
LRG_1074p2:p.Ile160Val
NC_000007.13:g.44190563T>C
NM_000162.3:c.475A>G

Protein change:

I158V

Links:

dbSNP: rs1319364468

NCBI 1000 Genomes Browser:

rs1319364468

Molecular consequence:

NM_000162.5:c.475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.478A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.472A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cowden syndrome (CS)
Synonyms:: Cowden's disease; Cowden's syndrome; Cowden disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0016063; MedGen: C0018553; Orphanet: 201; OMIM: PS158350

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005040813	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Mar 1, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29056535, 30257192 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005040813

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Mar 1, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

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

Insights into pathogenesis of five novel GCK mutations identified in Chinese MODY patients.

Liu L, Liu Y, Ge X, Liu X, Chen C, Wang Y, Li M, Yin J, Zhang J, Chen Y, Zhang R, Jiang Y, Zhao W, Yang D, Zheng T, Lu M, Zhuang L, Jiang M.

Metabolism. 2018 Dec;89:8-17. doi: 10.1016/j.metabol.2018.09.004. Epub 2018 Sep 23.

PubMed [citation]

PMID:: 30257192

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005040813.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: PTEN c.475A>G (p.Arg159Gly) results in a non-conservative amino acid change located in the phosphatase domain (IPR029023) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250998 control chromosomes (gnomAD). c.475A>G has been reported in the literature in at least one individual affected with Cowden Syndrome (CS) or CS-like phenotype (Tan_2011). These data do not allow clear conclusions about variant significance. One publication reported experimental evidence and demonstrated that the variant protein expressed in mammalian cells resulted in increased levels of Akt1 phosphorylation (Andres-Pons_2007). In addition, another variant affecting the same amino acid (R159T) was reported to be found in a patient affected with CS or CS-like phenotype (HGMD, Tan_2011), further supporting a functional role for the affected residue. One ClinVar submitter (evaluation after 2014) cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was 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: Jul 7, 2024

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