NM_006516.4(SLC2A1):c.929C>T (p.Thr310Ile) AND Childhood onset GLUT1 deficiency syndrome 2

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: May 4, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001089897.4

Allele description [Variation Report for NM_006516.4(SLC2A1):c.929C>T (p.Thr310Ile)]

NM_006516.4(SLC2A1):c.929C>T (p.Thr310Ile)

Gene:

SLC2A1:solute carrier family 2 member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.2

Genomic location:

Preferred name:

NM_006516.4(SLC2A1):c.929C>T (p.Thr310Ile)

Other names:

NM_006516.3:c.929C>T

HGVS:

NC_000001.11:g.42929253G>A
NG_008232.1:g.34924C>T
NM_006516.4:c.929C>TMANE SELECT
NP_006507.2:p.Thr310Ile
LRG_1132:g.34924C>T
NC_000001.10:g.43394924G>A
NM_006516.2:c.929C>T

Protein change:

T310I

Links:

dbSNP: rs80359824

NCBI 1000 Genomes Browser:

rs80359824

Molecular consequence:

NM_006516.4:c.929C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Childhood onset GLUT1 deficiency syndrome 2
Synonyms:: PAROXYSMAL EXERCISE-INDUCED DYSKINESIA WITH OR WITHOUT EPILEPSY AND/OR HEMOLYTIC ANEMIA; PAROXYSMAL EXERTION-INDUCED DYSTONIA WITH OR WITHOUT EPILEPSY AND/OR HEMOLYTIC ANEMIA; PED WITH OR WITHOUT EPILEPSY AND/OR HEMOLYTIC ANEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012805; MedGen: C1842534; Orphanet: 98811; OMIM: 612126

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001244290	Génétique des Maladies du Développement, Hospices Civils de Lyon	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002507091	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 4, 2022)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 10227690, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001244290

Génétique des Maladies du Développement, Hospices Civils de Lyon

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

de novo

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002507091

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 4, 2022)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Defective glucose transport across brain tissue barriers: a newly recognized neurological syndrome.

Klepper J, Wang D, Fischbarg J, Vera JC, Jarjour IT, O'Driscoll KR, De Vivo DC.

Neurochem Res. 1999 Apr;24(4):587-94.

PubMed [citation]

PMID:: 10227690

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Génétique des Maladies du Développement, Hospices Civils de Lyon, SCV001244290.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV002507091.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

The heterozygous p.Thr310Ile variant in SLC2A1 was identified by our study in 1 individual with childhood onset GLUT1 deficiency syndrome 2. This variant is assumed de novo in 2 individuals, but maternity and paternity have not been confirmed (PMID: 10227690, 33126486). The variant has been reported in 2 individuals of unknown ethnicity with childhood onset GLUT1 deficiency syndrome 2 (PMID: 10227690, 25616474), but was absent from large population studies. In vitro functional studies provide some evidence that the p.Thr310Ile variant may impact protein function (PMID: 14673082, 10227690, 12032147). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_moderate, PM2, PM6, PP3, PS4_supporting (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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