rs13306758
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_006516.4(SLC2A1):c.1372C>T(p.Arg458Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R458P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_006516.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC2A1 | NM_006516.4 | c.1372C>T | p.Arg458Trp | missense_variant | 10/10 | ENST00000426263.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC2A1 | ENST00000426263.10 | c.1372C>T | p.Arg458Trp | missense_variant | 10/10 | 1 | NM_006516.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Encephalopathy due to GLUT1 deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
GLUT1 deficiency syndrome 1, autosomal recessive Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 458 of the SLC2A1 protein (p.Arg458Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with generalized epilepsy (PMID: 23280796, 23340081, 28116237). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 96708). 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 expected to disrupt SLC2A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC2A1 function (PMID: 23280796). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 22, 2020 | Published functional studies demonstrate a marked reduction in glucose transport (Arsov et al., 2012; Zaman et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25564316, 29303961, 23340081, 23280796, 28717674, 30588498, 27779742, 30895386, 31710770, 30714351) - |
Dystonia 9;C1837206:Hereditary cryohydrocytosis with reduced stomatin;C1842534:Childhood onset GLUT1 deficiency syndrome 2;C3553859:Epilepsy, idiopathic generalized, susceptibility to, 12;C4551966:Encephalopathy due to GLUT1 deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Epilepsy, idiopathic generalized, susceptibility to, 12 Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Nov 01, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at