VCV000016143.6 - ClinVar

NM_000162.5(GCK):c.1367C>T (p.Ala456Val)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000162.5(GCK):c.1367C>T (p.Ala456Val)

Variation ID: 16143 Accession: VCV000016143.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p13 7: 44145167 (GRCh38) [ NCBI UCSC ] 7: 44184766 (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	Apr 4, 2013	Feb 14, 2024	Jan 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000162.5:c.1367C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000153.1:p.Ala456Val	missense
NM_001354800.1:c.1367C>T	NP_001341729.1:p.Ala456Val	missense
NM_001354801.1:c.356C>T	NP_001341730.1:p.Ala119Val	missense
NM_001354802.1:c.227C>T	NP_001341731.1:p.Ala76Val	missense
NM_001354803.2:c.401C>T	NP_001341732.1:p.Ala134Val	missense
NM_033507.3:c.1370C>T	NP_277042.1:p.Ala457Val	missense
NM_033508.3:c.1364C>T	NP_277043.1:p.Ala455Val	missense
NC_000007.14:g.44145167G>A
NC_000007.13:g.44184766G>A
NG_008847.2:g.58004C>T
LRG_1074:g.58004C>T
LRG_1074t1:c.1367C>T	LRG_1074p1:p.Ala456Val
LRG_1074t2:c.1370C>T	LRG_1074p2:p.Ala457Val

... more HGVS ... less HGVS

Protein change

A456V, A457V, A455V, A76V, A119V, A134V

Other names

Canonical SPDI

NC_000007.14:44145166:G: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

ClinGen: CA257433 OMIM: 138079.0012 dbSNP: rs104894014 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.
Hyperinsulinism due to glucokinase deficiency	Pathogenic (1)	no assertion criteria provided	Apr 1, 2002	RCV000017525.28
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 28, 2023	RCV001818166.6

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 (Dec 12, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002069051.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Pathogenic (Jan 28, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004295117.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 11916951‚ 15987895‚ 17082186‚ 17353190‚ 19146401‚ 21831042‚ 22194744‚ 14687251 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 11916951, 15987895, 17082186, … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 11916951, 15987895, 17082186, 17353190, 19146401, 21831042, 22194744). 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: 16143). This missense change has been observed in individuals with hyperinsulinemic hypoglycemia (PMID: 11916951, 14687251). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 456 of the GCK protein (p.Ala456Val). (less)
Pathogenic (Apr 01, 2002)	no assertion criteria provided Method: literature only	HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000037797.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 11916951 Comment on evidence: In a 14-year-old obese boy with a history of neonatal hypoglycemia treated with diazoxide, who was experiencing hypoglycemic episodes associated with seizures and unconsciousness (see … (more) In a 14-year-old obese boy with a history of neonatal hypoglycemia treated with diazoxide, who was experiencing hypoglycemic episodes associated with seizures and unconsciousness (see HHF3, 602485), Christesen et al. (2002) identified heterozygosity for an ala456-to-val (A456V) substitution in exon 10 of the GCK gene. Kinetic analysis showed this to be an activating mutation. The boy's normal-weight mother, who had asymptomatic fasting hypoglycemia, carried the same mutation; the mutation was not found in his normoglycemic brother nor in 80 controls. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 11916951, 15987895, 17082186, 17353190, 19146401, 21831042, 22194744). 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: 16143). This missense change has been observed in individuals with hyperinsulinemic hypoglycemia (PMID: 11916951, 14687251). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 456 of the GCK protein (p.Ala456Val).

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
Liver Glucokinase(A456V) Induces Potent Hypoglycemia without Dyslipidemia through a Paradoxical Induction of the Catalytic Subunit of Glucose-6-Phosphatase.	Vidal-Alabró A	International journal of endocrinology	2011	PMID: 22194744
Mutational analysis of allosteric activation and inhibition of glucokinase.	Zelent B	The Biochemical journal	2011	PMID: 21831042
Activating mutations in the human glucokinase gene revealed by genetic selection.	Pal P	Biochemistry	2009	PMID: 19146401
Glucokinase thermolability and hepatic regulatory protein binding are essential factors for predicting the blood glucose phenotype of missense mutations.	Pino MF	The Journal of biological chemistry	2007	PMID: 17353190
Biochemical basis of glucokinase activation and the regulation by glucokinase regulatory protein in naturally occurring mutations.	Heredia VV	The Journal of biological chemistry	2006	PMID: 17082186
Structure-function analysis of the alpha5 and the alpha13 helices of human glucokinase: description of two novel activating mutations.	Pedelini L	Protein science : a publication of the Protein Society	2005	PMID: 15987895
Family with autosomal dominant hyperinsulinism associated with A456V mutation in the glucokinase gene.	Dullaart RP	Journal of internal medicine	2004	PMID: 14687251
The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy.	Christesen HB	Diabetes	2002	PMID: 11916951

Text-mined citations for rs104894014 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000162.5(GCK):c.1367C>T (p.Ala456Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894014 ...