chr1-42930754-C-T

Variant names:

• chr1-42930754-C-T
• rs80359819
• NM_006516.4:c.388G>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.388G>A​(p.Gly130Ser) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G130A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC2A1 NM_006516.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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, 8 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 chr1-42930753-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2836371.Status of the report is criteria_provided_single_submitter, 1 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, 0.991
• PP5: Variant 1-42930754-C-T is Pathogenic according to our data. Variant chr1-42930754-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 627587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-42930754-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC2A1	NM_006516.4	c.388G>A	p.Gly130Ser	missense_variant	Exon 4 of 10	ENST00000426263.10	NP_006507.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC2A1	ENST00000426263.10	c.388G>A	p.Gly130Ser	missense_variant	Exon 4 of 10	1	NM_006516.4	ENSP00000416293.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455316 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724332

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Encephalopathy due to GLUT1 deficiency Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GLUT1 deficiency syndrome 1, autosomal recessive Pathogenic:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the SLC2A1 protein (p.Gly130Ser). 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: 15622525, 26982753, 30588498). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 627587). 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 with a positive predictive value of 95%. This variant disrupts the p.Gly130 amino acid residue in SLC2A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Nov 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate impaired function, as glucose transport was markedly decreased compared to wild type (Zaman et al., 2018); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23448551, 30895386, 20630673, 20129935, 24847886, 15622525, 26982753, 30588498, 26193382, 18387950, 29303961, 28556183) -

GLUT1 deficiency syndrome Pathogenic:1

Apr 27, 2018

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.6	D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.92		Loss of catalytic residue at V131 (P = 0.2013);.;
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80359819; hg19: chr1-43396425;