Published functional studies demonstrate kinetic inactivation with a decreased rate of catalysis and reduced affinity for glucose (Garca-Herrero et al., 2012; Valentnov et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 22291974, 17573900, 16965331, 30663027, 31216263, 33294763, 33565752, 32041611, 28726111, 34789499, Mustafa_2019[Article], 34746319, 26123671, 22493702, 21437567, 11508276)
ClinVar Genomic variation as it relates to human health
NM_000162.5(GCK):c.667G>A (p.Gly223Ser)
Germline
Classification
Help
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.
(9)
Help
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
9
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.667G>A (p.Gly223Ser)
Variation ID: 435306 Accession: VCV000435306.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7p13 7: 44149772 (GRCh38) [ NCBI UCSC ] 7: 44189371 (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 Aug 28, 2017 Oct 8, 2024 Feb 21, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000162.5:c.667G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000153.1:p.Gly223Ser missense NM_001354800.1:c.667G>A NP_001341729.1:p.Gly223Ser missense NM_033507.3:c.670G>A NP_277042.1:p.Gly224Ser missense NM_033508.3:c.664G>A NP_277043.1:p.Gly222Ser missense NC_000007.14:g.44149772C>T NC_000007.13:g.44189371C>T NG_008847.2:g.53399G>A LRG_1074:g.53399G>A LRG_1074t1:c.667G>A LRG_1074p1:p.Gly223Ser LRG_1074t2:c.670G>A LRG_1074p2:p.Gly224Ser - Protein change
- G223S, G224S, G222S
- Other names
- -
- Canonical SPDI
- NC_000007.14:44149771:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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
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 | ||
|---|---|---|---|---|---|---|
| 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 |
1091 | 1117 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 24, 2023 | RCV000517681.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763585.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 31, 2016 | RCV000502130.8 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 21, 2024 | RCV002367690.6 | |
|
GCK-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Apr 18, 2024 | RCV004751574.1 |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 27, 2023 | RCV003403165.1 |
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
(Aug 31, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
MODY, type II
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000594959.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity-onset diabetes of the young type 2
Type 2 diabetes mellitus Hyperinsulinism due to glucokinase deficiency Permanent neonatal diabetes mellitus 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894424.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Aug 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002559475.2
First in ClinVar: Aug 15, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate kinetic inactivation with a decreased rate of catalysis and reduced affinity for glucose (Garca-Herrero et al., 2012; Valentnov et al., 2012); … (more)
Published functional studies demonstrate kinetic inactivation with a decreased rate of catalysis and reduced affinity for glucose (Garca-Herrero et al., 2012; Valentnov et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 22291974, 17573900, 16965331, 30663027, 31216263, 33294763, 33565752, 32041611, 28726111, 34789499, Mustafa_2019[Article], 34746319, 26123671, 22493702, 21437567, 11508276) (less)
|
|
|
Pathogenic
(Oct 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Monogenic diabetes
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122238.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: GCK c.667G>A (p.Gly223Ser) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five … (more)
Variant summary: GCK c.667G>A (p.Gly223Ser) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251410 control chromosomes (gnomAD). c.667G>A has been reported in the literature in multiple individuals affected with Maturity-onset diabetes of the young (Valentnov_2012, Garcia-Herrero_2012, Delvecchio_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and variant effect results in <10% of normal activity (Garcia-Herrero_2012). The following publications have been ascertained in the context of this evaluation (PMID: 11508276, 16965331, 17573900, 25414397, 22291974, 22493702). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000613448.6
First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024 |
Comment:
This variant segregates with disease in multiple families with clinical features of MODY (PMID: 21437567, 22291974, 22493702) and was also identified in one individual with … (more)
This variant segregates with disease in multiple families with clinical features of MODY (PMID: 21437567, 22291974, 22493702) and was also identified in one individual with PNDM (PMID: 26123671). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant reduces glucokinase activity (PMID: 22291974, 22493702). (less)
|
|
|
Pathogenic
(Nov 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002245936.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict … (more)
This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies have shown that this missense change affects GCK function (PMID: 22291974, 22493702). 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: 435306). This missense change has been observed in individuals with autosomal dominant GCK-related conditions (PMID: 21437567, 31216263, 32041611, 33294763, 33565752). It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 223 of the GCK protein (p.Gly223Ser). (less)
|
|
|
Pathogenic
(May 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002663328.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.G223S pathogenic mutation (also known as c.667G>A), located in coding exon 6 of the GCK gene, results from a G to A substitution at … (more)
The p.G223S pathogenic mutation (also known as c.667G>A), located in coding exon 6 of the GCK gene, results from a G to A substitution at nucleotide position 667. The glycine at codon 223 is replaced by serine, an amino acid with similar properties. This mutation has been identified in numerous individuals ith maturity-onset diabetes of the young, segregating with disease (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26; Borowiec M et al. Acta Diabetol, 2011 Sep;48:203-8; García-Herrero CM et al. PLoS ONE, 2012 Jan;7:e30518; Valentínová L et al. PLoS ONE, 2012 Apr;7:e34541; Capuano M et al. PLoS ONE, 2012 Jun;7:e38906). This mutation was also identified in a compound heterozygous infant with persistent neonatal diabetes (Borowiec M et al. Acta Diabetol, 2011 Sep;48:203-8; Antosik K et al. Acta Diabetol, 2016 Apr;53:337-8). In addition, a GST fusion protein with this alteration expressed in E. coli demonstrated activity levels <10% of wild type with altered kinetics (García-Herrero CM et al. PLoS ONE, 2012 Jan;7:e30518). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Feb 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity onset diabetes mellitus in young
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847449.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Gly222Ser variant in GCK has been reported in the heterozygous state in at least 7 individuals with MODY and segregated with disease in 10 … (more)
The p.Gly222Ser variant in GCK has been reported in the heterozygous state in at least 7 individuals with MODY and segregated with disease in 10 affected individuals from 1 family (Valentinova 2012 PMID 22493702, Capuano 2012 PMID 22761713, Delvecchio 2014 PMID 25414397, Antosik 2016 PMID 26123671, Aloi 2017 PMID 28726111, Scully 2020 PMID 33294763). It was also identified in 1/1111930 European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0). This variant has also been reported in ClinVar (Variation ID 435306). In vitro functional studies, computational prediction tools, and conservation analyses support that this variant may impact the protein (Valentinova 2012 PMID 22493702). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria Applied: PS4, PP1_Strong, PM2_Supporting, PP3, PS3_Supporting. (less)
|
|
|
Pathogenic
(Apr 18, 2024)
|
no assertion criteria provided
Method: clinical testing
|
GCK-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005362520.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The GCK c.667G>A variant is predicted to result in the amino acid substitution p.Gly223Ser. This variant has been reported to be causative for maturity onset … (more)
The GCK c.667G>A variant is predicted to result in the amino acid substitution p.Gly223Ser. This variant has been reported to be causative for maturity onset diabetes of the young (MODY) due to impaired kinetic characteristics of glucokinase (Borowiec et al. 2011. PubMed ID: 21437567; García-Herrero et al. 2012. PubMed ID: 22291974). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
Variant summary: GCK c.667G>A (p.Gly223Ser) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251410 control chromosomes (gnomAD). c.667G>A has been reported in the literature in multiple individuals affected with Maturity-onset diabetes of the young (Valentnov_2012, Garcia-Herrero_2012, Delvecchio_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and variant effect results in <10% of normal activity (Garcia-Herrero_2012). The following publications have been ascertained in the context of this evaluation (PMID: 11508276, 16965331, 17573900, 25414397, 22291974, 22493702). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant segregates with disease in multiple families with clinical features of MODY (PMID: 21437567, 22291974, 22493702) and was also identified in one individual with PNDM (PMID: 26123671). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant reduces glucokinase activity (PMID: 22291974, 22493702).
Comment:
This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies have shown that this missense change affects GCK function (PMID: 22291974, 22493702). 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: 435306). This missense change has been observed in individuals with autosomal dominant GCK-related conditions (PMID: 21437567, 31216263, 32041611, 33294763, 33565752). It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 223 of the GCK protein (p.Gly223Ser).
Comment:
The p.G223S pathogenic mutation (also known as c.667G>A), located in coding exon 6 of the GCK gene, results from a G to A substitution at nucleotide position 667. The glycine at codon 223 is replaced by serine, an amino acid with similar properties. This mutation has been identified in numerous individuals ith maturity-onset diabetes of the young, segregating with disease (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26; Borowiec M et al. Acta Diabetol, 2011 Sep;48:203-8; García-Herrero CM et al. PLoS ONE, 2012 Jan;7:e30518; Valentínová L et al. PLoS ONE, 2012 Apr;7:e34541; Capuano M et al. PLoS ONE, 2012 Jun;7:e38906). This mutation was also identified in a compound heterozygous infant with persistent neonatal diabetes (Borowiec M et al. Acta Diabetol, 2011 Sep;48:203-8; Antosik K et al. Acta Diabetol, 2016 Apr;53:337-8). In addition, a GST fusion protein with this alteration expressed in E. coli demonstrated activity levels <10% of wild type with altered kinetics (García-Herrero CM et al. PLoS ONE, 2012 Jan;7:e30518). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The p.Gly222Ser variant in GCK has been reported in the heterozygous state in at least 7 individuals with MODY and segregated with disease in 10 affected individuals from 1 family (Valentinova 2012 PMID 22493702, Capuano 2012 PMID 22761713, Delvecchio 2014 PMID 25414397, Antosik 2016 PMID 26123671, Aloi 2017 PMID 28726111, Scully 2020 PMID 33294763). It was also identified in 1/1111930 European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0). This variant has also been reported in ClinVar (Variation ID 435306). In vitro functional studies, computational prediction tools, and conservation analyses support that this variant may impact the protein (Valentinova 2012 PMID 22493702). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria Applied: PS4, PP1_Strong, PM2_Supporting, PP3, PS3_Supporting.
Comment:
The GCK c.667G>A variant is predicted to result in the amino acid substitution p.Gly223Ser. This variant has been reported to be causative for maturity onset diabetes of the young (MODY) due to impaired kinetic characteristics of glucokinase (Borowiec et al. 2011. PubMed ID: 21437567; García-Herrero et al. 2012. PubMed ID: 22291974). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted 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:
Published functional studies demonstrate kinetic inactivation with a decreased rate of catalysis and reduced affinity for glucose (Garca-Herrero et al., 2012; Valentnov et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 22291974, 17573900, 16965331, 30663027, 31216263, 33294763, 33565752, 32041611, 28726111, 34789499, Mustafa_2019[Article], 34746319, 26123671, 22493702, 21437567, 11508276)
Comment:
Variant summary: GCK c.667G>A (p.Gly223Ser) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251410 control chromosomes (gnomAD). c.667G>A has been reported in the literature in multiple individuals affected with Maturity-onset diabetes of the young (Valentnov_2012, Garcia-Herrero_2012, Delvecchio_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and variant effect results in <10% of normal activity (Garcia-Herrero_2012). The following publications have been ascertained in the context of this evaluation (PMID: 11508276, 16965331, 17573900, 25414397, 22291974, 22493702). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant segregates with disease in multiple families with clinical features of MODY (PMID: 21437567, 22291974, 22493702) and was also identified in one individual with PNDM (PMID: 26123671). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant reduces glucokinase activity (PMID: 22291974, 22493702).
Comment:
This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies have shown that this missense change affects GCK function (PMID: 22291974, 22493702). 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: 435306). This missense change has been observed in individuals with autosomal dominant GCK-related conditions (PMID: 21437567, 31216263, 32041611, 33294763, 33565752). It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 223 of the GCK protein (p.Gly223Ser).
Comment:
The p.G223S pathogenic mutation (also known as c.667G>A), located in coding exon 6 of the GCK gene, results from a G to A substitution at nucleotide position 667. The glycine at codon 223 is replaced by serine, an amino acid with similar properties. This mutation has been identified in numerous individuals ith maturity-onset diabetes of the young, segregating with disease (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26; Borowiec M et al. Acta Diabetol, 2011 Sep;48:203-8; García-Herrero CM et al. PLoS ONE, 2012 Jan;7:e30518; Valentínová L et al. PLoS ONE, 2012 Apr;7:e34541; Capuano M et al. PLoS ONE, 2012 Jun;7:e38906). This mutation was also identified in a compound heterozygous infant with persistent neonatal diabetes (Borowiec M et al. Acta Diabetol, 2011 Sep;48:203-8; Antosik K et al. Acta Diabetol, 2016 Apr;53:337-8). In addition, a GST fusion protein with this alteration expressed in E. coli demonstrated activity levels <10% of wild type with altered kinetics (García-Herrero CM et al. PLoS ONE, 2012 Jan;7:e30518). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The p.Gly222Ser variant in GCK has been reported in the heterozygous state in at least 7 individuals with MODY and segregated with disease in 10 affected individuals from 1 family (Valentinova 2012 PMID 22493702, Capuano 2012 PMID 22761713, Delvecchio 2014 PMID 25414397, Antosik 2016 PMID 26123671, Aloi 2017 PMID 28726111, Scully 2020 PMID 33294763). It was also identified in 1/1111930 European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0). This variant has also been reported in ClinVar (Variation ID 435306). In vitro functional studies, computational prediction tools, and conservation analyses support that this variant may impact the protein (Valentinova 2012 PMID 22493702). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria Applied: PS4, PP1_Strong, PM2_Supporting, PP3, PS3_Supporting.
Comment:
The GCK c.667G>A variant is predicted to result in the amino acid substitution p.Gly223Ser. This variant has been reported to be causative for maturity onset diabetes of the young (MODY) due to impaired kinetic characteristics of glucokinase (Borowiec et al. 2011. PubMed ID: 21437567; García-Herrero et al. 2012. PubMed ID: 22291974). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Monogenic diabetes clinic (MDC): 3-year experience. | Rapini N | Acta diabetologica | 2023 | PMID: 36178555 |
| Identification of Novel GCK and HNF4α Gene Variants in Japanese Pediatric Patients with Onset of Diabetes before 17 Years of Age. | Katashima R | Journal of diabetes research | 2021 | PMID: 34746319 |
| The Application of Next Generation Sequencing Maturity Onset Diabetes of the Young Gene Panel in Turkish Patients from Trakya Region. | Yalçıntepe S | Journal of clinical research in pediatric endocrinology | 2021 | PMID: 33565752 |
| Monogenic Diabetes in a Child with Cystic Fibrosis: A Case Report and Review of the Literature. | Scully KJ | Journal of the Endocrine Society | 2020 | PMID: 33294763 |
| Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. | Dron JS | BMC medical genomics | 2020 | PMID: 32041611 |
| Maturity onset diabetes of the young (MODY) in Chinese children: genes and clinical phenotypes. | Ming-Qiang Z | Journal of pediatric endocrinology & metabolism : JPEM | 2019 | PMID: 31216263 |
| Glucokinase mutations in pediatric patients with impaired fasting glucose. | Aloi C | Acta diabetologica | 2017 | PMID: 28726111 |
| Single patient in GCK-MODY family successfully re-diagnosed into GCK-PNDM through targeted next-generation sequencing technology. | Antosik K | Acta diabetologica | 2016 | PMID: 26123671 |
| Low prevalence of HNF1A mutations after molecular screening of multiple MODY genes in 58 Italian families recruited in the pediatric or adult diabetes clinic from a single Italian hospital. | Delvecchio M | Diabetes care | 2014 | PMID: 25414397 |
| Glucokinase (GCK) mutations and their characterization in MODY2 children of southern Italy. | Capuano M | PloS one | 2012 | PMID: 22761713 |
| Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia. | Valentínová L | PloS one | 2012 | PMID: 22493702 |
| Functional characterization of MODY2 mutations highlights the importance of the fine-tuning of glucokinase and its role in glucose sensing. | García-Herrero CM | PloS one | 2012 | PMID: 22291974 |
| Detection of glucokinase gene defects in non-obese Japanese children diagnosed with diabetes by school medical examinations. | Yokota I | Endocrine journal | 2011 | PMID: 21720051 |
| Phenotype variability and neonatal diabetes in a large family with heterozygous mutation of the glucokinase gene. | Borowiec M | Acta diabetologica | 2011 | PMID: 21437567 |
| Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. | Osbak KK | Human mutation | 2009 | PMID: 19790256 |
| Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain. | Estalella I | Clinical endocrinology | 2007 | PMID: 17573900 |
| Identification of novel and recurrent glucokinase mutations in Belgian and Luxembourg maturity onset diabetes of the young patients. | Vits L | Clinical genetics | 2006 | PMID: 16965331 |
| Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY). | Thomson KL | Human mutation | 2003 | PMID: 14517956 |
| High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI. | Massa O | Diabetologia | 2001 | PMID: 11508276 |
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Text-mined citations for rs1360415315 ...
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Record last updated Oct 13, 2024
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