rs80359832

chr1-42930634-TGAG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_006516.4(SLC2A1):c.505_507del(p.Leu169del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L169L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC2A1 NM_006516.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.95

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 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_006516.4
• PM4: Nonframeshift variant in NON repetitive region in NM_006516.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-42930634-TGAG-T is Pathogenic according to our data. Variant chr1-42930634-TGAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 419011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC2A1	NM_006516.4	c.505_507del	p.Leu169del	inframe_deletion	4/10	ENST00000426263.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC2A1	ENST00000426263.10	c.505_507del	p.Leu169del	inframe_deletion	4/10	1	NM_006516.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Encephalopathy due to GLUT1 deficiency Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 18, 2023	Criteria applied: PS4_MOD,PM4,PM6,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Childhood onset GLUT1 deficiency syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dystonia 9 (MIM#601042), infantile-onset GLUT1 deficiency syndrome 1 (MIM#606777), childhood-onset GLUT1 deficiency syndrome 2 (GDS) (MIM#612126) and stomatin-deficient cryohydrocytosis with neurologic defects, (MIM#608885). (I) 0107 - This gene is associated with autosomal dominant disease. Autosomal recessive disease has been rarely reported (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Individuals with missense variants causing GDS or epilepsy have been reported with incomplete penetrance, but this is a rare occurrence (OMIM, PMID: 18451999). (I) 0115 - Variants in this gene are known to have variable expressivity within families with GDS (PMID: 20129935). (I) 0213 - In-frame deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in multiple individuals with early onset refractory seizures and/or GLUT1 deficiency syndrome. The variant in two of these individuals was confirmed de novo (ClinVar, PMID: 30271476, PMID: 20129935, PMID: 26193382). (SP) 1102 - Strong phenotype match for this individual. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

GLUT1 deficiency syndrome 1, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2021

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 419011). This variant is also known as 684-686delCTC. This variant, c.505_507del, results in the deletion of 1 amino acid(s) of the SLC2A1 protein (p.Leu169del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant glucose transporter deficiency syndrome (PMID: 15622525, 20129935, 31302675). In at least one individual the variant was observed to be de novo. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2017

The c.505_507delCTC pathogenic variant in the SLC2A1 gene has been reported multiple times previously (as 686delCTC or 684-686delCTC due to alternative nomenclature) in association with glucose transporter type 1 deficiency syndrome (Glut1-DS) (Pascual et al., 2002; Wang et al., 2005;). The c.505_507delCTC variant causes an in-frame deletion of a Leucine residue at codon 169, denoted p.Leu169del. The c.505_507delCTC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs80359832; hg19: chr1-43396305;