Early onset or syndromic epilepsy

Gene: SLC12A5

Green List (high evidence)

Comment on mode of inheritance: There are 4 individuals reported in literature with heterozygous SLC12A5 variants and generalised epilepsy. However, two of them harboured a common p.Arg952His variant; the other two variants also had multiple hets reported in gnomAD. Monoallelic variants are more likely to confer a susceptibility - there is little evidence for a dominant Mendelian disorder. Hence, the mode of inheritance should be changed to BIALLELIC only. An expert_review rating was added to ensure GMS agreement on this change.

Created: 10 Sep 2026, 2:11 p.m. | Last Modified: 10 Sep 2026, 2:13 p.m.

Panel Version: 9.81

MONOALLELIC REPORTS:
PMID: 24668262 Puskarjov et al., 2014
Study analyzed 378 (266 unrelated) patients with seizure disorders.
Variant NM_020708.4: c.2855G>A, p.Arg952His was reported in a large Australian pedigree with febrile seizures and noted to segregate with disease. However, the variant is common in gnomAD v4 (MAF = 0.01873, 42 hmz reported).

PMID: 24928908 Kahle et al., 2014
Idiopathic generalized epilepsy cohort. Variants c.2855G>A (p.R952H) and c.3145 C>T (p.R1049C) in SLC12A5 were reported. R952H is called a 'susceptibility' variant for febrile seizures in the article.
Variant p.R1049C has 33 hets and MAF = 0.0001537 in gnomAD v4, no homozygotes.

PMID: 31104500 Till et al., 2019
Male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy. WES detected a het SLC12A5:c.1348G>A, p.Val450Ile variant. 15 hets reported in gnomAD v4. [Article mostly in Hungarian]

SLC12A5 is robustly associated with AR Developmental and epileptic encephalopathy, with many patients reported in literature harbouring biallelic variants and their het parents being unaffected. Additional recessive case reports:
PMID: 28477354 Saito et al., 2017 - proband with comp het variants in SLC12A5 - maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5
PMID: 38660387 Järvelä et al., 2024 - proband homozygous for SLC12A5 c.692G>A, p.(R231H)
PMID: 42033187 Hamze et al., 2026 - 2 probands with unique comp het SLC12A5 variants (3 missense and 1 splice variant)

Created: 10 Sep 2026, 12:27 p.m. | Last Modified: 10 Sep 2026, 2:05 p.m.

Panel Version: 9.81

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
{Epilepsy, idiopathic generalized, susceptibility to, 14}, OMIM:616685; Developmental and epileptic encephalopathy 34, OMIM:616645

Publications

• 24668262
• 24928908
• 28477354
• 38660387
• 42033187

Green List (high evidence)

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

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

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

• 26333769
• 27436767

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

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

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

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

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.