VCV000429293.16 - ClinVar

NM_003042.4(SLC6A1):c.1084G>A (p.Gly362Arg)

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.

(9)

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/Likely 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_003042.4(SLC6A1):c.1084G>A (p.Gly362Arg)

Variation ID: 429293 Accession: VCV000429293.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.3 3: 11028740 (GRCh38) [ NCBI UCSC ] 3: 11070426 (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	Jul 2, 2017	Feb 14, 2024	Oct 16, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_003042.4:c.1084G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003033.3:p.Gly362Arg	missense
NM_001348250.2:c.1084G>A	NP_001335179.1:p.Gly362Arg	missense
NM_001348251.2:c.724G>A	NP_001335180.1:p.Gly242Arg	missense
NM_001348252.2:c.550G>A	NP_001335181.1:p.Gly184Arg	missense
NM_001348253.2:c.550G>A	NP_001335182.1:p.Gly184Arg	missense
NC_000003.12:g.11028740G>A
NC_000003.11:g.11070426G>A
NG_053003.1:g.41012G>A

... more HGVS ... less HGVS

Protein change

G362R, G184R, G242R

Other names

Canonical SPDI

NC_000003.12:11028739: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: CA351790791 dbSNP: rs1131691302 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.
SLC6A1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	674	965

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.
not provided	Pathogenic (3)	criteria provided, single submitter	Nov 3, 2021	RCV000494060.6
Neurodevelopmental delay	Pathogenic (1)	criteria provided, single submitter	-	RCV002274042.2
Myoclonic-astatic epilepsy	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 15, 2022	RCV003444555.5
Myoclonic-atonic epilepsy	Pathogenic (1)	criteria provided, single submitter	Oct 16, 2022	RCV003596006.2

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.
Likely pathogenic (Nov 24, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myoclonic-atonic epilepsy Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002044464.1 First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022	Comment: _x000D_ Criteria applied: PS2_MOD, PS4_MOD, PM1, PM2_SUP, PP3
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental delay Affected status: yes Allele origin: inherited	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV002559105.1 First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022
Pathogenic (Mar 26, 2021)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Myoclonic-atonic epilepsy (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV002764891.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Cerebellar ataxia (present) , Hypotonia (present) , Delayed speech and language development (present)
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000581823.6 First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect … (more) Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 29315614, 33310157, 26716362, 34006619) (less)
Likely pathogenic (Sep 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myoclonic-atonic epilepsy Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807409.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PS4 moderated, PM1 moderated, PM2 moderated, PP3 supporting Number of individuals with the variant: 1 Clinical Features: Maternal hypertension (present) , Attention deficit hyperactivity disorder (present) , Intellectual disability, moderate (present) , Generalized non-motor (absence) seizure (present) , Hyperpigmented/hypopigmented macules (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Oct 16, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Myoclonic-atonic epilepsy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001581156.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 26716362‚ 29315614 Comment: For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more) For these reasons, this variant has been classified as Pathogenic. 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 SLC6A1 protein function. ClinVar contains an entry for this variant (Variation ID: 429293). This missense change has been observed in individual(s) with clinical features of SLC6A1-related conditions (PMID: 26716362, 29315614; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 362 of the SLC6A1 protein (p.Gly362Arg). (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001799628.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807864.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
not provided (-)	no classification provided Method: phenotyping only	Myoclonic-atonic epilepsy Affected status: yes Allele origin: de novo	GenomeConnect - Brain Gene Registry Accession: SCV004012835.1 First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023	Comment: Variant interpreted as Likely pathogenic and reported on 05-05-2017 by Lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. … (more) Variant interpreted as Likely pathogenic and reported on 05-05-2017 by Lab GeneDx. 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 Dr. Philip Payne 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: Atonic seizure (present) , Seizure (present) , Hypotonia (present) , Cerebellar ataxia (present) , EEG abnormality (present) , Global developmental delay (present) Indication for testing: Diagnostic Age: 0-9 years Sex: male Method: Exome Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2017-05-05 Testing laboratory interpretation: Likely pathogenic

Comment:

Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 29315614, 33310157, 26716362, 34006619)

Comment:

For these reasons, this variant has been classified as Pathogenic. 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 SLC6A1 protein function. ClinVar contains an entry for this variant (Variation ID: 429293). This missense change has been observed in individual(s) with clinical features of SLC6A1-related conditions (PMID: 26716362, 29315614; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 362 of the SLC6A1 protein (p.Gly362Arg).

Comment:

Variant interpreted as Likely pathogenic and reported on 05-05-2017 by Lab GeneDx. 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 Dr. Philip Payne 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
Defining the phenotypic spectrum of SLC6A1 mutations.	Johannesen KM	Epilepsia	2018	PMID: 29315614
Mosaic mutations in early-onset genetic diseases.	Halvorsen M	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26716362

Text-mined citations for rs1131691302 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_003042.4(SLC6A1):c.1084G>A (p.Gly362Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1131691302 ...