rs892715050
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP2PP3_Strong
The ENST00000426263.10(SLC2A1):c.1001G>A(p.Arg334Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,488 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334W) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000426263.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC2A1 | NM_006516.4 | c.1001G>A | p.Arg334Gln | missense_variant | 8/10 | ENST00000426263.10 | NP_006507.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC2A1 | ENST00000426263.10 | c.1001G>A | p.Arg334Gln | missense_variant | 8/10 | 1 | NM_006516.4 | ENSP00000416293 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461270Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727014
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74366
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 08, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | - - |
Dystonia 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 19, 2020 | The alteration results in an amino acid change:_x000D_ _x000D_ The c.1001G>A (p.R334Q) alteration is located in exon 8 (coding exon 8) of the SLC2A1 gene. This alteration results from a G to A substitution at nucleotide position 1001, causing the arginine (R) at amino acid position 334 to be replaced by a glutamine (Q). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the SLC2A1 c.1001G>A alteration was not observed, with coverage at this position. A nearby alteration has been observed in affected individuals: _x000D_ _x000D_ Alaterations in an adjacent amino acid (p.R333), have been described in multiple patients with various phenotypes caused by GLUT1 deficiency. Mullen et al. (2011) reported two patients heterozygous for c.997C>T (p.R333W) myoclonic astatic epilepsy, paroxysmal exercise induced dyskinesia, dysarthric speech, intellectual disability, and low CSF glucose.This alteration was reported in two Japanese individuals; a 6 year old female with mild developmental delay, ataxic gait, myocloni seizures, and mild hypotonia (Takahasi, 2008) and a 2 year old boy with tonic seizures, developmental delay, cerebral atrophy, ataxic gait, and low CSF glucose (Fujii, 2007); both demonstrated dramatic improvement on a ketogenic diet (Fujii, 2007; Takahasi, 2008). Schneider et al. (2009) reported a 43 year old man with paroxysmal exercise induced dyskinesia who was heterozygous for the c.998G>A (p.R333Q) alteration; he had a history of jerky leg spasms at 4 years old following physical exercise, exercise-induced writer's cramp after prolonged writing, and myoclonic epilepsy in childhood. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R334 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.R334Q alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Encephalopathy due to GLUT1 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Childhood onset GLUT1 deficiency syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
GLUT1 deficiency syndrome 1, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 13, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 334 of the SLC2A1 protein (p.Arg334Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SLC2A1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 520805). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt SLC2A1 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cryohydrocytosis with reduced stomatin Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Epilepsy, idiopathic generalized, susceptibility to, 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at