NM_006516.4:c.1408G>T
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP2BP4
The NM_006516.4(SLC2A1):c.1408G>T(p.Gly470Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G470R) has been classified as Likely benign.
Frequency
Consequence
NM_006516.4 missense
Scores
Clinical Significance
Conservation
Publications
- encephalopathy due to GLUT1 deficiencyInheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
- GLUT1 deficiency syndromeInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- childhood onset GLUT1 deficiency syndrome 2Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
- dystonia 9Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- epilepsy, idiopathic generalized, susceptibility to, 12Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- childhood absence epilepsyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary cryohydrocytosis with reduced stomatinInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- myoclonic-astatic epilepsyInheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152172Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000279 AC: 7AN: 251076 AF XY: 0.0000295 show subpopulations
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461888Hom.: 1 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727244 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74460 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2
p.Gly470Trp (G470W) GGG>TGG: c.1408 G>T in exon 10 of the SLC2A1 gene (NM_006516.2) The G470W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G470W variant is a semi-D2 conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across mammals but is not conserved in more distantly related species in evolution. A missense mutation in a nearby residue (R468W) has been reported in association with Glut1-DS. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the possibility that it is a disease-associated mutation cannot be excluded since some individuals with SLC2A1 mutations have been reported to be mildly affected or unaffected due to variability in phenotypic expression and/or reduced penetrance (Mullen et al., 2010; Weber et al., 2008; Suls et al., 2008). The variant is found in EPILEPSY panel(s). -
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Dystonia 9 Uncertain:1
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Encephalopathy due to GLUT1 deficiency Uncertain:1
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Childhood onset GLUT1 deficiency syndrome 2 Uncertain:1
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GLUT1 deficiency syndrome 1, autosomal recessive Uncertain:1
ClinVar contains an entry for this variant (Variation ID: 207217). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC2A1 protein function. This variant has not been reported in the literature in individuals affected with SLC2A1-related conditions. 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. This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 470 of the SLC2A1 protein (p.Gly470Trp). This variant is present in population databases (rs572648977, gnomAD 0.02%). -
Hereditary cryohydrocytosis with reduced stomatin Uncertain:1
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Epilepsy, idiopathic generalized, susceptibility to, 12 Uncertain:1
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Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at