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Genetic epilepsy syndromes

Gene: SLC12A5

Green List (high evidence)

SLC12A5 (solute carrier family 12 member 5)
EnsemblGeneIds (GRCh38): ENSG00000124140
EnsemblGeneIds (GRCh37): ENSG00000124140
OMIM: 606726, Gene2Phenotype
SLC12A5 is in 4 panels

8 reviews

Helen Lord (Oxford Medical Genetics Laboratories)

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Rebecca Foulger (Genomics England curator)

I don't know

Comment on mode of inheritance: Changed Mode of Inheritance from 'BOTH monoallelic and bialleic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' based on post-Webex review by Helen Lord.
Created: 7 Sep 2019, 11:50 a.m. | Last Modified: 7 Sep 2019, 11:50 a.m.
Panel Version: 1.288
Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.
Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262
Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.
Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189

Tracy Lester (Genetics laboratory, Oxford UK)

Green List (high evidence)

AR EIEE34 & AD generalised idiopathic epilepsy 14. AR EIEE34 - Stodberg et al, 2015 - 4 children from 2 unrelated families - hom/compound het variants in these families - in vitro studies showed that the nutations caused decreased membrane expression, impaired posttrnslational modification and a loss of transporter function resulting in impaired normal synaptic inhibition and promition if neuronal excitability. AD epilepsy - Kahle et al, 2014 - 380 epilepsy patients - 8 patients of French Canadian origin had two diff missense variants (5 - R952H & 3 - R1049C). In vitro expression studies showed that the variants impaired the functon of SLC12A5. Puskarjov et al, 2014 - 3 aff family members in an Australian family - R952H. In vitro studies also done - support pathogenicity.
Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, early infantile, 616645; {Epilepsy, idiopathic generalized, susceptibility to}; 616685

Publications

Amy McTague (UCL Institute of Child Health)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

  • Stodberg et al (2015) Nat. Commun. 6:8038 doi: 10.1038/ncomms9038

Variants in this GENE are reported as part of current diagnostic practice

Natalie Trump (NHS - Great Ormond Street Hospital)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

  • Stodberg et al (2015) Nat. Commun. 6:8038 doi: 10.1038/ncomms9038

Variants in this GENE are reported as part of current diagnostic practice

Manju Kurian (UCL-Institute of Child Health)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

  • Stodberg et al (2015) Nat. Commun. 6:8038 doi: 10.1038/ncomms9038

Variants in this GENE are reported as part of current diagnostic practice

Richard Scott (North Thames GMC/UCL)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

  • Stodberg et al (2015) Nat. Commun. 6:8038 doi: 10.1038/ncomms9038

Variants in this GENE are reported as part of current diagnostic practice

Ellen McDonagh (Genomics England Curator)

Comment on mode of inheritance: Both applies to information from reviewers, G2P and OMIM, and publications.
Created: 29 Jan 2016, 5:10 p.m.
PMID: 25839329 - Two families, each with two children with EIMFS with similar presentation, were investigated. Missense mutations within the SLC12A5 gene were reported in all four children, with a recessive mode of inheritance. The children from Family A were compound heterozygotes for missense mutations c.1277T>C (L426P) and c.1652G>A (G551D). The affected patients from Family B were homozygous for the missense variant c.932T>A (L311H). Parents were heterozygous carriers. No potential pathogenic variants were found in known EIMFS or EIEE genes in the families. Postulated mechanism from in vitro/in vivo studies is through reduced surface expression, impairing normal synaptic inhibition and promoting neuronal excitability.

PMID: 24668262 - 378 patients with seizure disorders were analyzed and 11 rare variants in SLC12A% were identified. In one family, rs142740233 NM_020708.4:c.2855G>A missense variant (causing Arg>His at position 952 in KCC2b and 975 in KCC2a) was found. The KCC2b isoform of the variant (named KCC2-R952H) was investigated further and was shown to result in reduced cell surface expression.
Created: 21 Jan 2016, 1:51 p.m.
Comment on phenotypes: From PMID: 26333769
Created: 21 Jan 2016, 1:12 p.m.

Details

Mode of Inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Wessex and West Midlands GLH
  • NHS GMS
  • Victorian Clinical Genetics Services
  • Expert Review
Phenotypes
  • epilepsy of infancy with migrating focal seizures (EIMFS)
  • Epileptic encephalopathy, early infantile, 34, 616645
  • {Epilepsy, idiopathic generalized, susceptibility to, 14}, 616685
OMIM
606726
Clinvar variants
Variants in SLC12A5
Penetrance
None
Publications
Panels with this gene

History Filter Activity

7 Sep 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: slc12a5 has been classified as Green List (High Evidence).

7 Sep 2019, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: SLC12A5 were changed from epilepsy of infancy with migrating focal seizures (EIMFS) to epilepsy of infancy with migrating focal seizures (EIMFS); Epileptic encephalopathy, early infantile, 34, 616645; {Epilepsy, idiopathic generalized, susceptibility to, 14}, 616685

7 Sep 2019, Gel status: 3

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: SLC12A5 were set to PMID: 26333769; 24668262

7 Sep 2019, Gel status: 3

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: SLC12A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

7 Sep 2019, Gel status: 3

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: SLC12A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to SLC12A5.

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to SLC12A5.

11 Dec 2018, Gel status: 4

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Ellen McDonagh: Comment on phenotypes: From PM

25 Jun 2018, Gel status: 4

Added New Source

Sarah Leigh (Genomics England Curator)

Victorian Clinical Genetics Services was added to SLC12A5. Panel: Genetic Epilepsy Syndromes

4 Apr 2018, Gel status: 4

Added New Source

Sarah Leigh (Genomics England Curator)

SLC12A5 was added to Genetic Epilepsy Syndromes panel. Sources: Expert Review Green,Expert Review

4 Apr 2018, Gel status: 4

Created

Sarah Leigh (Genomics England Curator)

SLC12A5 was created by Sarah Leigh