Submissions for variant NM_006516.4(SLC2A1):c.766_767delinsGT (p.Lys256Val)

dbSNP: rs80359822

Total submissions: 9

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000017488	SCV001205061	uncertain significance	GLUT1 deficiency syndrome 1, autosomal recessive	2024-05-16	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with valine, which is neutral and non-polar, at codon 256 of the SLC2A1 protein (p.Lys256Val). This variant is present in population databases (rs80359822, gnomAD 0.001%). This missense change has been observed in individual(s) with SLC2A1-related conditions (PMID: 20687207). ClinVar contains an entry for this variant (Variation ID: 16108). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SLC2A1 function (PMID: 21069159). 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.
Genome-Nilou Lab	RCV003445074	SCV004172948	uncertain significance	Epilepsy, idiopathic generalized, susceptibility to, 12	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003445073	SCV004172949	uncertain significance	Dystonia 9	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002271986	SCV004172950	uncertain significance	Encephalopathy due to GLUT1 deficiency	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003445072	SCV004172951	uncertain significance	Childhood onset GLUT1 deficiency syndrome 2	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003445075	SCV004172952	uncertain significance	Hereditary cryohydrocytosis with reduced stomatin	2023-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV000017488	SCV000037760	pathogenic	GLUT1 deficiency syndrome 1, autosomal recessive	2010-12-01	no assertion criteria provided	literature only
GeneReviews	RCV002271986	SCV002556354	not provided	Encephalopathy due to GLUT1 deficiency		no assertion provided	literature only