1-42930766-G-A

Variant names:

• chr1-42930766-G-A
• rs80359818
• NM_006516.4:c.376C>T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_006516.4(SLC2A1):​c.376C>T​(p.Arg126Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000242987: Published functional studies demonstrate a damaging effect by significantly impairing glucose transport (Wong et al., 2007; Suls et al., 2009; Zaman et al., 2018); SCV000649804: Experimental studies have shown that this missense change affects SLC2A1 function (PMID:17052934, 19798636).; SCV006423556: "In multiple assays testing SLC2A1 function, this variant showed functionally abnormal results" (Zaman, 2018; Suls, 2008).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R126L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC2A1 NM_006516.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 7.99
• Publications: 33 publications found

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]

SLC2A1 Gene-Disease associations (from GenCC):

• encephalopathy due to GLUT1 deficiency

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• GLUT1 deficiency syndrome

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
• childhood onset GLUT1 deficiency syndrome 2

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• dystonia 9

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• epilepsy, idiopathic generalized, susceptibility to, 12

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• childhood absence epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary cryohydrocytosis with reduced stomatin

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000242987: Published functional studies demonstrate a damaging effect by significantly impairing glucose transport (Wong et al., 2007; Suls et al., 2009; Zaman et al., 2018); SCV000649804: Experimental studies have shown that this missense change affects SLC2A1 function (PMID: 17052934, 19798636).; SCV006423556: "In multiple assays testing SLC2A1 function, this variant showed functionally abnormal results" (Zaman, 2018; Suls, 2008).
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr1-42930765-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16109.Status of the report is no_assertion_criteria_provided, 0 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 encephalopathy due to GLUT1 deficiency, GLUT1 deficiency syndrome, childhood onset GLUT1 deficiency syndrome 2, myoclonic-astatic epilepsy, hereditary cryohydrocytosis with reduced stomatin, dystonia 9, childhood absence epilepsy, epilepsy, idiopathic generalized, susceptibility to, 12.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 1-42930766-G-A is Pathogenic according to our data. Variant chr1-42930766-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006516.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A1	NM_006516.4	MANE Select	c.376C>T	p.Arg126Cys	missense	Exon 4 of 10	NP_006507.2	P11166

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A1	ENST00000426263.10	TSL:1 MANE Select	c.376C>T	p.Arg126Cys	missense	Exon 4 of 10	ENSP00000416293.2	P11166
	SLC2A1	ENST00000889577.1		c.373C>T	p.Arg125Cys	missense	Exon 4 of 10	ENSP00000559636.1
	SLC2A1	ENST00000958848.1		c.376C>T	p.Arg126Cys	missense	Exon 4 of 10	ENSP00000628907.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 244362 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453098 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 723286

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111936

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Encephalopathy due to GLUT1 deficiency (5)
3	-	-	not provided (3)
2	-	-	Hereditary cryohydrocytosis with reduced stomatin (2)
1	-	-	Childhood onset GLUT1 deficiency syndrome 2 (1)
1	-	-	Chromosome 17q23.1-q23.2 deletion syndrome (1)
1	-	-	Dystonia 9 (1)
1	-	-	GLUT1 deficiency syndrome 1, autosomal recessive (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	SLC2A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.98		Loss of methylation at R126 (P = 0.0505)
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs80359818; hg19: chr1-43396437;