NM_000162.5(GCK):c.1019+18G>A AND not specified

Germline classification:: Benign/Likely benign (3 submissions)
Last evaluated:: Oct 3, 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:: RCV000418514.5

Allele description [Variation Report for NM_000162.5(GCK):c.1019+18G>A]

NM_000162.5(GCK):c.1019+18G>A

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.1019+18G>A

HGVS:

NC_000007.14:g.44146445C>T
NG_008847.2:g.56726G>A
NM_000162.5:c.1019+18G>AMANE SELECT
NM_001354800.1:c.1019+18G>A
NM_001354801.1:c.8+174G>A
NM_033507.3:c.1022+18G>A
NM_033508.3:c.1016+18G>A
LRG_1074t1:c.1019+18G>A
LRG_1074t2:c.1022+18G>A
LRG_1074:g.56726G>A
NC_000007.13:g.44186044C>T
NM_000162.3:c.1019+18G>A
NM_000162.5:c.1019+18G>A

Links:

dbSNP: rs150914617

NCBI 1000 Genomes Browser:

rs150914617

Molecular consequence:

NM_000162.5:c.1019+18G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354800.1:c.1019+18G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354801.1:c.8+174G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_033507.3:c.1022+18G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_033508.3:c.1016+18G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000513129	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Jan 7, 2016)	germline	clinical testing	Citation Link,
SCV004121941	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Oct 3, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14517946, 15928245, 10447526, 18271687, 19515026, 23275527 Citation Link,
SCV004848490	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Nov 6, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000513129

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Jan 7, 2016)

germline

clinical testing

Citation Link,

SCV004121941

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Oct 3, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV004848490

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(Nov 6, 2020)

germline

clinical testing

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

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

Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy.

Gloyn AL.

Hum Mutat. 2003 Nov;22(5):353-62. Review.

PubMed [citation]

PMID:: 14517946

Half of clinically defined maturity-onset diabetes of the young patients in Denmark do not have mutations in HNF4A, GCK, and TCF1.

Johansen A, Ek J, Mortensen HB, Pedersen O, Hansen T.

J Clin Endocrinol Metab. 2005 Aug;90(8):4607-14. Epub 2005 May 31.

PubMed [citation]

PMID:: 15928245

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000513129.4

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004121941.1

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

Description

Variant summary: GCK c.1019+18G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Three computational tools predict that the variant abolishes a cryptic 5' splicing donor site but does not affect the canonical splice site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0032 in 239030 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 126-fold of the estimated maximal expected allele frequency for a pathogenic variant in GCK causing Monogenic Diabetes phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1019+18G>A has been reported in the literature in individuals affected with diabetes and hyperinsulinism without evidence of cosegregation with disease (e.g. Lehto_1999, Johansen_2005, Lukasova_2008, Odem_2009, Snider_2013). These reports do not provide unequivocal conclusions about association of the variant with Monogenic Diabetes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10447526, 14517946, 15928245, 18271687, 19515026, 23275527). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848490.1

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

Description

The c.1016+18G>A variant in GCK classified as benign because it has been identified in 0.5% (660/125912) of European chromosomes, including 2 homozygote occurences, by gnomAD (http://gnomad.broadinstitute.org). In additon, it is not located within the splice consensus sequence and computational splice prediction tools predict disruption of a cryptic splice at this position without effect on the canonical splice. It has been reported in ClinVar (Variation ID: 377918). ACMG/AMP Criteria applied: BS1, BP4, BP7.

#	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: Sep 29, 2024

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