VCV000585915.5 - ClinVar

NM_000162.5(GCK):c.1327G>T (p.Glu443Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

4 submissions

4 submitters

3 conditions

Reviewed by expert panel

Pathogenic

Sep 2023 by ClinGen Monoge… FDA Recognized Database

for Monogenic diabetes

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000162.5(GCK):c.1327G>T (p.Glu443Ter)

Variation ID: 585915 Accession: VCV000585915.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p13 7: 44145207 (GRCh38) [ NCBI UCSC ] 7: 44184806 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 20, 2018	Jan 6, 2024	Sep 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000162.5:c.1327G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000153.1:p.Glu443Ter	nonsense
NM_001354800.1:c.1327G>T	NP_001341729.1:p.Glu443Ter	nonsense
NM_001354801.1:c.316G>T	NP_001341730.1:p.Glu106Ter	nonsense
NM_001354802.1:c.187G>T	NP_001341731.1:p.Glu63Ter	nonsense
NM_001354803.2:c.361G>T	NP_001341732.1:p.Glu121Ter	nonsense
NM_033507.3:c.1330G>T	NP_277042.1:p.Glu444Ter	nonsense
NM_033508.3:c.1324G>T	NP_277043.1:p.Glu442Ter	nonsense
NC_000007.14:g.44145207C>A
NC_000007.13:g.44184806C>A
NG_008847.2:g.57964G>T
LRG_1074:g.57964G>T
LRG_1074t1:c.1327G>T	LRG_1074p1:p.Glu443Ter
LRG_1074t2:c.1330G>T	LRG_1074p2:p.Glu444Ter

... more HGVS ... less HGVS

Protein change

E443*, E444*, E63*, E106*, E121*, E442*

Other names

NM_000162.5(GCK):c.1327G>T
p.Glu443Ter

Canonical SPDI

NC_000007.14:44145206:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs1562711915 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GCK		-	-	GRCh38 GRCh37	1120	1146

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 3, 2018	RCV000711766.3
Monogenic diabetes	Pathogenic (2)	reviewed by expert panel	Sep 1, 2023	RCV001844229.4
Maturity onset diabetes mellitus in young	Pathogenic (1)	criteria provided, single submitter	-	RCV002463729.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 01, 2023)	reviewed by expert panel (ClinGen Monogenic Diabetes ACMG Specifications GCK V1.3.0) Method: curation	Monogenic diabetes (Semidominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Monogenic Diabetes Variant Curation Expert Panel FDA Recognized Database Accession: SCV004032112.1 First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5409829d-3e29-4e50-b8ef-0cecc6917dee Comment: The c.1327G>T variant in the glucokinase gene, GCK causes a premature stop codon in the protein at codon 443 (NM_000162.5). While this variant, located in … (more) The c.1327G>T variant in the glucokinase gene, GCK causes a premature stop codon in the protein at codon 443 (NM_000162.5). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID:19790256). This variant was identified in 4 unrelated individuals with a clinical picture consistent with monogenic diabetes (PS4_Moderate; PMID: 20337973, PMID: 32901087, ClinVar ID 585915), including at least one individual with a clinical history suggestive of GCK-MODY but with insufficient clinical information provided to evaluate for PP4. In summary, c.1327G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PS4_Moderate, PM2_Supporting. (less)
Pathogenic (Jan 03, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000842160.1 First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018
Pathogenic (-)	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1) Method: research	Maturity onset diabetes mellitus in young (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV002605050.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Publications: PubMed (6) PubMed: 33129248‚ 27269892‚ 32375122‚ 31197960‚ 30257192‚ 29510678 Comment: Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet … (more) Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1562711915 in MODY, yet. (less)
Pathogenic (Nov 03, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Monogenic diabetes Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002103382.2 First in ClinVar: Mar 12, 2022 Last updated: Jan 06, 2024	Comment: Variant summary: GCK c.1327G>T (p.Glu443X) results in a premature termination codon and is not predicted to cause nonsense mediated decay, but is expected to result … (more) Variant summary: GCK c.1327G>T (p.Glu443X) results in a premature termination codon and is not predicted to cause nonsense mediated decay, but is expected to result in a truncation of the encoded protein, a commonly known mechanism for disease. Variants downstream of this position have been classified as pathogenic by our laboratory and others in ClinVar. The variant was absent in 242994 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1327G>T in individuals affected with Monogenic Diabetes and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Two submitters, including the ClinGen Monogenic Diabetes Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)

Comment:

The c.1327G>T variant in the glucokinase gene, GCK causes a premature stop codon in the protein at codon 443 (NM_000162.5). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID:19790256). This variant was identified in 4 unrelated individuals with a clinical picture consistent with monogenic diabetes (PS4_Moderate; PMID: 20337973, PMID: 32901087, ClinVar ID 585915), including at least one individual with a clinical history suggestive of GCK-MODY but with insufficient clinical information provided to evaluate for PP4. In summary, c.1327G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PS4_Moderate, PM2_Supporting.

Comment:

Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1562711915 in MODY, yet.

Comment:

Variant summary: GCK c.1327G>T (p.Glu443X) results in a premature termination codon and is not predicted to cause nonsense mediated decay, but is expected to result in a truncation of the encoded protein, a commonly known mechanism for disease. Variants downstream of this position have been classified as pathogenic by our laboratory and others in ClinVar. The variant was absent in 242994 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1327G>T in individuals affected with Monogenic Diabetes and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Two submitters, including the ClinGen Monogenic Diabetes Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical implications of the glucokinase impaired function - GCK MODY today.	Hulín J	Physiological research	2020	PMID: 33129248
MODY2 in Asia: analysis of GCK mutations and clinical characteristics.	Zhou Y	Endocrine connections	2020	PMID: 32375122
Association of a homozygous GCK missense mutation with mild diabetes.	Marucci A	Molecular genetics & genomic medicine	2019	PMID: 31197960
Insights into pathogenesis of five novel GCK mutations identified in Chinese MODY patients.	Liu L	Metabolism: clinical and experimental	2018	PMID: 30257192
Genetic and clinical characteristics of Chinese children with Glucokinase-maturity-onset diabetes of the young (GCK-MODY).	Li X	BMC pediatrics	2018	PMID: 29510678
GCK mutations in Chinese MODY2 patients: a family pedigree report and review of Chinese literature.	Ping Xiao Y	Journal of pediatric endocrinology & metabolism : JPEM	2016	PMID: 27269892
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5409829d-3e29-4e50-b8ef-0cecc6917dee	-	-	-	-

Text-mined citations for rs1562711915 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000162.5(GCK):c.1327G>T (p.Glu443Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1562711915 ...