Submissions for variant NM_006516.4(SLC2A1):c.694C>T (p.Arg232Cys)

dbSNP: rs387907313

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189356	SCV000242993	pathogenic	not provided	2014-05-15	criteria provided, single submitter	clinical testing	p.Arg232Cys (CGC>TGC): c.694 C>T in exon 6 of the SLC2A1 gene (NM_006516.2)The R232C mutation in the SLC2A1 gene was previously reported in multiple individuals from one family with idiopathic generalized epilepsy, predominantly characterized by absence seizures, and it was also detected in several unaffected family members consistent with reduced penetrance for this mutation (Striano et al., 2012). Functional studies indicate this mutation mildly impairs glucose transport (Striano et al., 2012). R232C was not detected in 846 normal control individuals, and the NHLBI ESP Exome Variant Project has not identified it in approximately 6,500 individuals of European or African American ethnicity (Striano et al., 2012; Exome Variant Project, 2014). The R232C mutation results in 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, and in silico algorithms predict R232C may be damaging to protein structure and function. It alters a highly conserved residue in the cytoplasmic loop between the sixth and seventh transmembrane domains, and missense mutations have been reported at other residues in this region of the protein in association with GLUT1 deficiency (Leen et al., 2010). The variant is found in EPILEPSY,CHILD-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001063268	SCV001228106	pathogenic	GLUT1 deficiency syndrome 1, autosomal recessive	2023-04-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC2A1 function (PMID: 22282645). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC2A1 protein function. ClinVar contains an entry for this variant (Variation ID: 37301). This missense change has been observed in individual(s) with idiopathic generalized epilepsy (PMID: 22282645; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs387907313, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 232 of the SLC2A1 protein (p.Arg232Cys).
CeGaT Center for Human Genetics Tuebingen	RCV000189356	SCV002062795	likely pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003445091	SCV004173307	likely pathogenic	Encephalopathy due to GLUT1 deficiency	2023-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV000030841	SCV000053516	risk factor	Epilepsy, idiopathic generalized, susceptibility to, 12	2012-02-21	no assertion criteria provided	literature only