VCV000421211.16 - ClinVar

NM_003042.4(SLC6A1):c.1531G>A (p.Val511Met)

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.

(6)

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.

Conflicting classifications of pathogenicity
Pathogenic(4); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003042.4(SLC6A1):c.1531G>A (p.Val511Met)

Variation ID: 421211 Accession: VCV000421211.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.3 3: 11034534 (GRCh38) [ NCBI UCSC ] 3: 11076220 (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	Apr 27, 2017	May 26, 2024	May 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003042.4:c.1531G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003033.3:p.Val511Met	missense
NM_001348250.2:c.1531G>A	NP_001335179.1:p.Val511Met	missense
NM_001348251.2:c.1171G>A	NP_001335180.1:p.Val391Met	missense
NM_001348252.2:c.997G>A	NP_001335181.1:p.Val333Met	missense
NM_001348253.2:c.997G>A	NP_001335182.1:p.Val333Met	missense
NC_000003.12:g.11034534G>A
NC_000003.11:g.11076220G>A
NG_053003.1:g.46806G>A

... more HGVS ... less HGVS

Protein change

V511M, V333M, V391M

Other names

Canonical SPDI

NC_000003.12:11034533: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: CA16617802 dbSNP: rs1064794981 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	678	971

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 (2)	criteria provided, single submitter	Sep 12, 2023	RCV000485887.4
not specified	Uncertain significance (1)	criteria provided, single submitter	May 3, 2017	RCV000517929.4
Neurodevelopmental delay	Pathogenic (1)	criteria provided, single submitter	-	RCV002274039.4
Seizure	Pathogenic (1)	criteria provided, single submitter	May 16, 2024	RCV004556060.2
Myoclonic-atonic epilepsy	Pathogenic (1)	criteria provided, single submitter	Nov 2, 2023	RCV003762748.2

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.
Uncertain significance (May 03, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000615329.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017
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: SCV002559036.1 First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022
Pathogenic (Sep 12, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000570338.4 First in ClinVar: Apr 27, 2017 Last updated: Sep 22, 2023	Comment: Published functional studies demonstrate a damaging effect (Mermer et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated … (more) Published functional studies demonstrate a damaging effect (Mermer et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29315614, 34028503, 34006619, 31440721, 31302675) (less)
Pathogenic (Nov 02, 2023)	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: SCV000956575.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 29315614‚ 31302675 Comment: This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 511 of the SLC6A1 protein (p.Val511Met). … (more) This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 511 of the SLC6A1 protein (p.Val511Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SLC6A1-related conditions (PMID: 29315614, 31302675; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421211). 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 not expected to disrupt SLC6A1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures Affected status: yes Allele origin: unknown	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV005045275.1 First in ClinVar: May 26, 2024 Last updated: May 26, 2024	Sex: male
Pathogenic (Jun 14, 2022)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Molecular Genetics laboratory, Necker Hospital Accession: SCV004031301.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Clinical Features: Intellectual disability (present)

Comment:

Published functional studies demonstrate a damaging effect (Mermer et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29315614, 34028503, 34006619, 31440721, 31302675)

Comment:

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 511 of the SLC6A1 protein (p.Val511Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SLC6A1-related conditions (PMID: 29315614, 31302675; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421211). 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 not expected to disrupt SLC6A1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

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
Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort.	Symonds JD	Brain : a journal of neurology	2019	PMID: 31302675
Defining the phenotypic spectrum of SLC6A1 mutations.	Johannesen KM	Epilepsia	2018	PMID: 29315614

Text-mined citations for rs1064794981 ...

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 19, 2024

ClinVar Genomic variation as it relates to human health

NM_003042.4(SLC6A1):c.1531G>A (p.Val511Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1064794981 ...