NM_003042.4(SLC6A1):c.913G>A (p.Ala305Thr) AND Myoclonic-atonic epilepsy

not current

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 9, 2023
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:: RCV003763931.2

Allele description

NM_003042.4(SLC6A1):c.913G>A (p.Ala305Thr)

Gene:

SLC6A1:solute carrier family 6 member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_003042.4(SLC6A1):c.913G>A (p.Ala305Thr)

HGVS:

NC_000003.12:g.11025836G>A
NG_053003.1:g.38108G>A
NM_001348250.2:c.913G>A
NM_001348251.2:c.553G>A
NM_001348252.2:c.379G>A
NM_001348253.2:c.379G>A
NM_003042.4:c.913G>AMANE SELECT
NP_001335179.1:p.Ala305Thr
NP_001335180.1:p.Ala185Thr
NP_001335181.1:p.Ala127Thr
NP_001335182.1:p.Ala127Thr
NP_003033.3:p.Ala305Thr
NC_000003.11:g.11067522G>A
NC_000003.11:g.11067522G>A
NM_003042.3:c.913G>A

Protein change:

A127T

Links:

dbSNP: rs1391625316

NCBI 1000 Genomes Browser:

rs1391625316

Molecular consequence:

NM_001348250.2:c.913G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001348251.2:c.553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001348252.2:c.379G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001348253.2:c.379G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003042.4:c.913G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Myoclonic-atonic epilepsy (MAE)
Identifiers:: MONDO: MONDO:0014633; MedGen: CN231318; Orphanet: 1942; OMIM: 616421

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002125571	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 9, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28135719, 31785789, 34006619, 28492532
SCV005042861	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002125571

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 9, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV005042861

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Prevalence and architecture of de novo mutations in developmental disorders.

Deciphering Developmental Disorders Study.

Nature. 2017 Feb 23;542(7642):433-438. doi: 10.1038/nature21062. Epub 2017 Jan 25.

PubMed [citation]

PMID:: 28135719
PMCID:: PMC6016744

Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders.

Turner TN, Wilfert AB, Bakken TE, Bernier RA, Pepper MR, Zhang Z, Torene RI, Retterer K, Eichler EE.

Am J Hum Genet. 2019 Dec 5;105(6):1274-1285. doi: 10.1016/j.ajhg.2019.11.003. Epub 2019 Nov 27.

PubMed [citation]

PMID:: 31785789
PMCID:: PMC6904808

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV002125571.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 305 of the SLC6A1 protein (p.Ala305Thr). 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: 28135719, 31785789, 34006619). ClinVar contains an entry for this variant (Variation ID: 976158). 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. This variant disrupts the p.Ala305 amino acid residue in SLC6A1. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

From Neuberg Centre For Genomic Medicine, NCGM, SCV005042861.1

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

Description

The missense variant c.913G>Ap.Ala305Thr in SLC6A1 gene has been reported previously de novo with Neurodevelopmental Disorders Deciphering Developmental Disorders Study, 2017, Turner et al., 2019. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance/ Likely Pathogenic. The amino acid Alanine at position 305 is changed to a Threonine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Ala305Thr in SLC6A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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

Last Updated: Sep 16, 2024

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