chr7-44149772-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000162.5(GCK):c.667G>A(p.Gly223Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G223R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000162.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.667G>A | p.Gly223Ser | missense_variant | 6/10 | ENST00000403799.8 | |
LOC105375258 | XR_927223.3 | n.303C>T | non_coding_transcript_exon_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.667G>A | p.Gly223Ser | missense_variant | 6/10 | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461720Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727162
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2022 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 24, 2023 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2022 | 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). - |
Maturity onset diabetes mellitus in young Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 17, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 21, 2024 | 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. - |
Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1833104:Permanent neonatal diabetes mellitus;C1865290:Hyperinsulinism due to glucokinase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Maturity-onset diabetes of the young type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 31, 2016 | - - |
Monogenic diabetes Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 27, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at