Submissions for variant NM_006516.4(SLC2A1):c.1199G>A (p.Arg400His)

dbSNP: rs776095655

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000364606	SCV000329808	pathogenic	not provided	2023-02-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30311381, 22976442, 21555602, 25487684, 30714351, 30700737, 31710770, 32712428, 36034301, 28116237)
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000678305	SCV000804364	pathogenic	Encephalopathy due to GLUT1 deficiency	2018-02-12	criteria provided, single submitter	provider interpretation	This variant was identified in a 5 year old female with infantile-onset seizures, esotropia, global developmental delays, movement disorder, and wide-based gait. It is inherited from a mother with intellectual disability and a diagnosis of paroxysmal dyskinesia. Since receiving this result, this patient has started ketogenic diet and has seen acceleration of developmental progress. Her seizures have stopped and she was weaned from anti-epileptic medication. This variant is absent from the gnomAD database and has been reported in other patients with Glut1DS (Mullen, 2011; Vieker, 2012; Ito, 2015). Other variants affecting this same codon have also been established as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694332	SCV000822772	pathogenic	GLUT1 deficiency syndrome 1, autosomal recessive	2022-01-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg400 amino acid residue in SLC2A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21865127, 28018440). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 280046). This missense change has been observed in individual(s) with GLUT1-deficiency syndrome (PMID: 21555602, 22976442, 25487684). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 400 of the SLC2A1 protein (p.Arg400His).
MGZ Medical Genetics Center	RCV000678305	SCV002581632	likely pathogenic	Encephalopathy due to GLUT1 deficiency	2022-08-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002347986	SCV002644862	likely pathogenic	Inborn genetic diseases	2017-09-29	criteria provided, single submitter	clinical testing	The p.R400H variant (also known as c.1199G>A), located in coding exon 9 of the SLC2A1 gene, results from a G to A substitution at nucleotide position 1199. The arginine at codon 400 is replaced by histidine, an amino acid with highly similar properties. This mutation has been reported in multiple individuals with clinical diagnoses of GLUT1 deficiency syndrome with a spectrum of clinical features (Mullen SA et al. Arch. Neurol., 2011 Sep;68:1152-5; Ito Y et al. Brain Dev., 2015 Sep;37:780-9; De Giorgis V et al. J. Child Neurol., 2016 Aug;31:1174-80). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genome-Nilou Lab	RCV000678305	SCV004172668	likely pathogenic	Encephalopathy due to GLUT1 deficiency	2023-04-11	criteria provided, single submitter	clinical testing