rs80359818
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_006516.4(SLC2A1):c.376C>T(p.Arg126Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging 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. R126L) has been classified as Pathogenic.
Frequency
Consequence
NM_006516.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC2A1 | NM_006516.4 | c.376C>T | p.Arg126Cys | missense_variant | 4/10 | ENST00000426263.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC2A1 | ENST00000426263.10 | c.376C>T | p.Arg126Cys | missense_variant | 4/10 | 1 | NM_006516.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.88e-7 AC: 1AN: 1453098Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 723286
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Encephalopathy due to GLUT1 deficiency Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 3-year-old female with static encephalopathy, developmental delay, hypotonia, seizures - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 06, 2011 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2020 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | SLC2A1: PM1, PM2, PM5, PS4:Moderate, PP3, PS2:Supporting, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 28, 2023 | Published functional studies demonstrate a damaging effect by significantly impairing glucose transport (Wong et al., 2007; Suls et al., 2009; Zaman et al., 2018); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19798636, 21546317, 17052934, 24847886, 27725288, 28717674, 12325075, 30588498, 29530121, 29655203, 31352161, 31440721, 28116237) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 11, 2013 | - - |
Hereditary cryohydrocytosis with reduced stomatin Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 19, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Dystonia 9 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 06, 2011 | - - |
Childhood onset GLUT1 deficiency syndrome 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 06, 2011 | - - |
GLUT1 deficiency syndrome 1, autosomal recessive Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 26, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 126 of the SLC2A1 protein (p.Arg126Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant GLUT1 deficiency syndrome (PMID: 17718830, 21546317, 26193382). ClinVar contains an entry for this variant (Variation ID: 16118). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SLC2A1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC2A1 function (PMID: 17052934, 19798636). This variant disrupts the p.Arg126 amino acid residue in SLC2A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17718830, 19798636, 26193382). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at