NM_000162.5(GCK):c.556C>T (p.Arg186Ter) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 23, 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:: RCV000516235.13

Allele description [Variation Report for NM_000162.5(GCK):c.556C>T (p.Arg186Ter)]

NM_000162.5(GCK):c.556C>T (p.Arg186Ter)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.556C>T (p.Arg186Ter)

HGVS:

NC_000007.14:g.44149992G>A
NG_008847.2:g.53179C>T
NM_000162.5:c.556C>TMANE SELECT
NM_001354800.1:c.556C>T
NM_033507.3:c.559C>T
NM_033508.3:c.553C>T
NP_000153.1:p.Arg186Ter
NP_001341729.1:p.Arg186Ter
NP_277042.1:p.Arg187Ter
NP_277043.1:p.Arg185Ter
LRG_1074t1:c.556C>T
LRG_1074t2:c.559C>T
LRG_1074:g.53179C>T
LRG_1074p1:p.Arg186Ter
LRG_1074p2:p.Arg187Ter
NC_000007.13:g.44189591G>A
NM_000162.3:c.556C>T
p.ARG186*

Protein change:

R185*; ARG186TER

Links:

OMIM: 138079.0002; dbSNP: rs104894006

NCBI 1000 Genomes Browser:

rs104894006

Molecular consequence:

NM_000162.5:c.556C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354800.1:c.556C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_033507.3:c.559C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_033508.3:c.553C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000613441	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Apr 13, 2017)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 1360036, 15841481, 17573900, 18271687, 8094164, 8433729, 9049484, 26467025
SCV000890276	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 28, 2022)	germline	clinical testing	Citation Link,
SCV002242623	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 23, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 7553875, 9867845, 14578306, 24323243, 25015100, 1360036, 30191644, 30257192, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000613441

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Apr 13, 2017)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000890276

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jul 28, 2022)

germline

clinical testing

Citation Link,

SCV002242623

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 23, 2023)

germline

clinical testing

PubMed (9)
[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

Identification of novel GCK and HNF1A/TCF1 mutations and polymorphisms in German families with maturity-onset diabetes of the young (MODY).

Toaima D, Näke A, Wendenburg J, Praedicow K, Rohayem J, Engel K, Galler A, Gahr M, Lee-Kirsch MA.

Hum Mutat. 2005 May;25(5):503-4.

PubMed [citation]

PMID:: 15841481

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 (16)

Details of each submission

From Athena Diagnostics, SCV000613441.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	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

From GeneDx, SCV000890276.4

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

Description

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 17573900, 18271687, 8094164, 1397713, 30257192, 8094163, 26641800, 27269892, 22060211, 8168652, 33046911, 15841481, 24952377, 19002431, 8433729, 24430320, 30191644, 20337973, 33852230, 21348868, 30665703, 9049484, 24660669, 32533152, 1360036)

#	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, SCV002242623.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change creates a premature translational stop signal (p.Arg186*) in the GCK gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCK are known to be pathogenic (PMID: 7553875, 9867845, 14578306, 24323243, 25015100). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with GCK-related conditions (PMID: 1360036, 30191644, 30257192). ClinVar contains an entry for this variant (Variation ID: 16133). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as 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 29, 2024

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