ClinVar Miner

Submissions for variant NM_006516.3(SLC2A1):c.766_767delinsGT (p.Lys256Val) (rs80359822)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189388 SCV000243026 uncertain significance not specified 2017-05-05 criteria provided, single submitter clinical testing A variant of unknown significance has been identified in the SLC2A1 gene. The c.766_767delAAinsGT variant was previously identified in an individual with features consistent with Glut-1 deficiency syndrome; however, it was inherited from the unaffected mother, and this individual also harbored another SLC2A1 missense variant that was de novo (Wang et al., 2000; Rotstein et al., 2010). The c.766_767delAAinsGT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.766_767delAAinsGT variant results in an in-frame deletion of a single Lysine residue and the insertion of a single Valine residue, denoted p.K256V. Functional studies have shown that K256V results in decreased glucose transport (Jiang et al., 2010). The K256V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae RCV000017488 SCV001205061 uncertain significance GLUT1 deficiency syndrome 1, autosomal recessive 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces lysine with valine at codon 256 of the SLC2A1 protein (p.Lys256Val). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another SLC2A1 variant (p.Arg126Leu, found de novo) in an individual affected with GLUT1 deficiency, and in heterozygosity in his asymptomatic mother. The proband in this family likely had autosomal dominant disease due to the presence of the de novo p.Arg126Leu variant, and the contribution of p.Lys256Val to the disease is unclear (PMID: 20687207). ClinVar contains an entry for this variant (Variation ID: 16108). This variant has been reported to have conflicting or insufficient data to determine the effect on SLC2A1 protein function (PMID: 21069159). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
OMIM RCV000017488 SCV000037760 pathogenic GLUT1 deficiency syndrome 1, autosomal recessive 2010-12-01 no assertion criteria provided literature only

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