VCV000207196.47 - ClinVar

NM_006516.4(SLC2A1):c.988C>T (p.Arg330Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006516.4(SLC2A1):c.988C>T (p.Arg330Ter)

Variation ID: 207196 Accession: VCV000207196.47

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.2 1: 42929018 (GRCh38) [ NCBI UCSC ] 1: 43394689 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 29, 2016	Oct 20, 2024	Apr 11, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006516.4:c.988C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006507.2:p.Arg330Ter	nonsense
NC_000001.11:g.42929018G>A
NC_000001.10:g.43394689G>A
NG_008232.1:g.35159C>T
LRG_1132:g.35159C>T

... more HGVS ... less HGVS

Protein change

R330*

Other names

p.R330*:CGA>TGA

Canonical SPDI

NC_000001.11:42929017:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA318438 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SLC2A1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1056	1097

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
GLUT1 deficiency syndrome 1, autosomal recessive	Pathogenic (1)	criteria provided, single submitter	Jul 25, 2022	RCV000461498.10
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jun 29, 2016	RCV000622452.3
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 1, 2021	RCV000189360.32
Encephalopathy due to GLUT1 deficiency	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 11, 2023	RCV000679880.5
Childhood onset GLUT1 deficiency syndrome 2 Dystonia 9 Encephalopathy due to GLUT1 deficiency Hereditary cryohydrocytosis with reduced stomatin	Pathogenic (1)	criteria provided, single submitter	Dec 15, 2017	RCV001249688.6
Epilepsy Microcephaly intellectual deficiency	Likely pathogenic (1)	no assertion criteria provided	-	RCV000415466.2
Childhood onset GLUT1 deficiency syndrome 2	Pathogenic (1)	criteria provided, single submitter	Jul 11, 2017	RCV001004692.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Encephalopathy due to GLUT1 deficiency (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Baylor Genetics Accession: SCV000807266.2 First in ClinVar: Sep 17, 2018 Last updated: Dec 11, 2022	Publications: PubMed (2) PubMed: 25326635‚ 10980529 Comment: This variant has been previously reported as disease-causing and was found once in our laboratory in a 13-year-old female with intellectual disability with regression, microcephaly, … (more) This variant has been previously reported as disease-causing and was found once in our laboratory in a 13-year-old female with intellectual disability with regression, microcephaly, cryptogenic generalized epilepsy, static encephalopathy (less)
Pathogenic (Jun 29, 2016)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741549.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Number of individuals with the variant: 1 Clinical Features: Epileptic encephalopathy (present) , Global developmental delay (present) , Seizures (present) Sex: female Ethnicity/Population group: Unknown
Pathogenic (Jul 25, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	GLUT1 deficiency syndrome 1, autosomal recessive Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000545826.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 10980529‚ 20129935‚ 26216499‚ 21832227‚ 26193382 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 207196). This premature translational stop signal has been observed in individual(s) with Glut-1 Deficiency Syndrome (PMID: 10980529, 20129935, 26216499). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg330*) in the SLC2A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC2A1 are known to be pathogenic (PMID: 21832227, 26193382). (less)
Pathogenic (Jul 11, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Childhood onset GLUT1 deficiency syndrome 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV001164153.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Publications: PubMed (1) PubMed: 10980529
Pathogenic (Oct 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001500364.23 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Encephalopathy due to GLUT1 deficiency Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004172800.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023
Pathogenic (Dec 15, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Encephalopathy due to GLUT1 deficiency Childhood onset GLUT1 deficiency syndrome 2 Dystonia 9 Hereditary cryohydrocytosis with reduced stomatin Affected status: yes Allele origin: germline	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV001423684.1 First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020	Comment: [ACMG/AMP: PVS1, PS2, PM2, PP3, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is … (more) [ACMG/AMP: PVS1, PS2, PM2, PP3, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. (less)
Pathogenic (Sep 04, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020696.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 01, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000242997.17 First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10980529, 25525159, 26216499, 26193382, 20129935, 29655203, 32371413, 34676189, 32712428) (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	Intellectual deficiency epilepsy microcephaly Affected status: yes Allele origin: de novo	Laboratory of Molecular Genetics, CHU Rennes Accession: SCV000493100.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017	Sex: female
not provided (-)	no classification provided Method: phenotyping only	Encephalopathy due to GLUT1 deficiency Affected status: unknown Allele origin: unknown	GenomeConnect - Brain Gene Registry Accession: SCV003804779.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: Variant interpreted as Pathogenic and reported on 07-25-2022 by Invitae . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect … (more) Variant interpreted as Pathogenic and reported on 07-25-2022 by Invitae . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Philip Payne PhD, FACMI from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less) Clinical Features: Cerebral palsy (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Movement disorder (present) , Short attention span (present) … (more) Cerebral palsy (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Movement disorder (present) , Short attention span (present) , Abnormal muscle physiology (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: female Method: Gene Panel Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2022-07-25 Testing laboratory interpretation: Pathogenic
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Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 207196). This premature translational stop signal has been observed in individual(s) with Glut-1 Deficiency Syndrome (PMID: 10980529, 20129935, 26216499). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg330*) in the SLC2A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC2A1 are known to be pathogenic (PMID: 21832227, 26193382).

Comment:

[ACMG/AMP: PVS1, PS2, PM2, PP3, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10980529, 25525159, 26216499, 26193382, 20129935, 29655203, 32371413, 34676189, 32712428)

Comment:

Variant interpreted as Pathogenic and reported on 07-25-2022 by Invitae . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Philip Payne PhD, FACMI from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
New Paradigm for the Treatment of Glucose Transporter 1 Deficiency Syndrome: Low Glycemic Index Diet and Modified High Amylopectin Cornstarch.	Almuqbil M	Pediatric neurology	2015	PMID: 26216499
From splitting GLUT1 deficiency syndromes to overlapping phenotypes.	Hully M	European journal of medical genetics	2015	PMID: 26193382
Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect.	Weber YG	Neurology	2011	PMID: 21832227
Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder.	Leen WG	Brain : a journal of neurology	2010	PMID: 20129935
Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome.	Wang D	Human mutation	2000	PMID: 10980529

Text-mined citations for this variant ...

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_006516.4(SLC2A1):c.988C>T (p.Arg330Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...