rs193922338
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000162.5(GCK):c.944T>A(p.Leu315His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,660 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. L315F) 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.944T>A | p.Leu315His | missense_variant | 8/10 | ENST00000403799.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.944T>A | p.Leu315His | missense_variant | 8/10 | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458660Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 725860
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 11, 2019 | DNA sequence analysis of the GCK gene demonstrated a sequence change, c.944T>A, in exon 8 that results in an amino acid change, p.Leu315His. This sequence change has been previously described in patients with GCK-related MODY in multiple unrelated family members and is one of the one of the most prevalent GCK mutations in the Czech population (PMIDs: 20337973, 22332836, 17204055). The p.Leu315His change affects a highly conserved amino acid residue located in a functional domain of the GCK protein that is known to be functional and other pathogenic variants have been described in this region. The p.Leu315His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies for this sequence change showed a severe loss of glucokinase activity (PMID: 26208450). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 02, 2022 | ClinVar contains an entry for this variant (Variation ID: 36266). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 16602010, 17204055, 22332836, 26552609). 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 leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 315 of the GCK protein (p.Leu315His). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCK function (PMID: 22493702, 26208450). - |
Maturity-onset diabetes of the young type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at