NM_006516.4:c.1199G>A

Variant names:

• chr1-42927684-C-T
• rs776095655
• NM_006516.4:c.1199G>A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_006516.4(SLC2A1):​c.1199G>A​(p.Arg400His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R400C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC2A1 NM_006516.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.91

Genes affected

SLC2A1 (HGNC:11005): (solute carrier family 2 member 1) This gene encodes a major glucose transporter in the mammalian blood-brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II. Mutations in this gene have been found in a family with paroxysmal exertion-induced dyskinesia. [provided by RefSeq, Apr 2013]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_006516.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-42927685-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 207212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the SLC2A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 98 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 2.9256 (below the threshold of 3.09). Trascript score misZ: 4.6729 (above the threshold of 3.09). GenCC associations: The gene is linked to childhood absence epilepsy, dystonia 9, epilepsy, idiopathic generalized, susceptibility to, 12, GLUT1 deficiency syndrome, myoclonic-astatic epilepsy, childhood onset GLUT1 deficiency syndrome 2, hereditary cryohydrocytosis with reduced stomatin, encephalopathy due to GLUT1 deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 1-42927684-C-T is Pathogenic according to our data. Variant chr1-42927684-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A1	NM_006516.4	c.1199G>A	p.Arg400His	missense_variant	Exon 9 of 10	ENST00000426263.10	NP_006507.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A1	ENST00000426263.10	c.1199G>A	p.Arg400His	missense_variant	Exon 9 of 10	1	NM_006516.4	ENSP00000416293.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Encephalopathy due to GLUT1 deficiency Pathogenic:3

Aug 02, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 12, 2018

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;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. -

Inborn genetic diseases Pathogenic:1

Sep 29, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

GLUT1 deficiency syndrome 1, autosomal recessive Pathogenic:1

Jan 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 280046). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Feb 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Gain of loop (P = 0.1069);
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs776095655; hg19: chr1-43393355;