NM_000162.5(GCK):c.952G>A (p.Gly318Arg) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jul 25, 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:: RCV000711789.10

Allele description [Variation Report for NM_000162.5(GCK):c.952G>A (p.Gly318Arg)]

NM_000162.5(GCK):c.952G>A (p.Gly318Arg)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.952G>A (p.Gly318Arg)

HGVS:

NC_000007.14:g.44146530C>T
NG_008847.2:g.56641G>A
NM_000162.5:c.952G>AMANE SELECT
NM_001354800.1:c.952G>A
NM_001354801.1:c.8+89G>A
NM_033507.3:c.955G>A
NM_033508.3:c.949G>A
NP_000153.1:p.Gly318Arg
NP_001341729.1:p.Gly318Arg
NP_277042.1:p.Gly319Arg
NP_277043.1:p.Gly317Arg
LRG_1074t1:c.952G>A
LRG_1074t2:c.955G>A
LRG_1074:g.56641G>A
LRG_1074p1:p.Gly318Arg
LRG_1074p2:p.Gly319Arg
NC_000007.13:g.44186129C>T
NM_000162.3:c.952G>A

Protein change:

G317R

Links:

dbSNP: rs193922340

NCBI 1000 Genomes Browser:

rs193922340

Molecular consequence:

NM_001354801.1:c.8+89G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000162.5:c.952G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354800.1:c.952G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033507.3:c.955G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_033508.3:c.949G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Bombyx mori p50ma DNA, chromosome 27, sequence
Bombyx mori p50ma DNA, chromosome 27, sequence
gi|2532299255|dbj|AP028197.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000842186	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Nov 23, 2021)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 28842611, 22289546, 24518839, 21521320, 28663157, 24660669, 26552609, 21348868, 23433541, 12627330, 22332836, 14517956, 16602010, 26467025
SCV002031111	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 22, 2022)	germline	clinical testing	Citation Link,
SCV002235363	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 25, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12627330, 22493702, 28663157, 29207974, 28492532
SCV002502879	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 16, 2022)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 21348868, 12627330, 14517956, 20337973, 28012402, 28663157, 26552609, 24518839, 22289546, 24918535, 28842611, 29207974, 22332836, 31416898, 30245511, 23433541, 34440516, 34556497, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	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

HDL cholesterol as a diagnostic tool for clinical differentiation of GCK-MODY from HNF1A-MODY and type 1 diabetes in children and young adults.

Fendler W, Borowiec M, Antosik K, Szadkowska A, Deja G, Jarosz-Chobot P, Mysliwiec M, Wyka K, Pietrzak I, Skupien J, Malecki MT, Mlynarski W.

Clin Endocrinol (Oxf). 2011 Sep;75(3):321-7. doi: 10.1111/j.1365-2265.2011.04052.x.

PubMed [citation]

PMID:: 21521320

Population-based estimates for double diabetes amongst people with glucokinase monogenic diabetes, GCK-MODY.

Fendler W, Małachowska B, Baranowska-Jazwiecka A, Borowiec M, Wyka K, Malecki MT, Jarosz-Chobot P, Mysliwiec M, Mlynarski W; PolPeDiab Study Group..

Diabet Med. 2014 Jul;31(7):881-3. doi: 10.1111/dme.12449. No abstract available.

PubMed [citation]

PMID:: 24660669

See all PubMed Citations (25)

Details of each submission

From Athena Diagnostics, SCV000842186.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduced affinity of the enzyme to glucose (PMID: 28842611).

#	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 GeneDx, SCV002031111.2

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

Description

Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21348868, 33852230, 26641800, 12627330, 14517956, 20337973, 28012402, 28663157, 26552609, 24518839, 22289546, 24918535, 28842611, 29207974, 31416898, 30245511, 23433541, 34440516, 34556497, 22332836)

#	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, SCV002235363.3

#	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 glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 318 of the GCK protein (p.Gly318Arg). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 585929). This missense change has been observed in individuals with maturity onset diabetes of the young (MODY) (PMID: 12627330, 22493702, 28663157, 29207974). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002502879.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (19)

#	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		1	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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