Early onset or syndromic epilepsy

Gene: ATP2B1

Green List (high evidence)

Comment on list classification: As previously reviewed, there are at least 6 individuals reported in literature with heterozygous ATP2B1 variants and a neurodevelopmental disorder including infantile spasms and febrile seizures (PMID: 35358416). In addition, 2 unrelated families presented with ATP2B1-related isolated epilepsy (PMID: 40834682). Heterozygous variants in ATP2B1 may lead to either syndromic or isolated early onset epilepsy. Hence, this gene should be promoted to Green on this panel.

Created: 30 Jan 2026, 10:53 a.m. | Last Modified: 30 Jan 2026, 10:54 a.m.

Panel Version: 8.99

PMID: 40834682 Zhu et al., 2025
Report of patient with de novo ATP2B1 c.2920A>G/p.Ile974Val and 4 family members with the same ATP2B1 splice variant c.76G>A/p.Asp26Asn). Method: trio WES.
The individuals presented with generalized epilepsy without neurodevelopmental disorders. Patient heterozygous for p.Ile974Val developed seizures at age 11 years, successfully medicated with lamotrigine. The individuals in family 2 had seizure onset at 3 months - 1 year, but the seizures resolved without medication before age 2 years.
c.2920A>G - 1 heterozygotes reported in gnomAD v4.1.0
c.76G>A - 6 heterozygotes reported in gnomAD v4.1.0

This gene is linked to Intellectual developmental disorder, autosomal dominant 66, OMIM:619910 in OMIM (accessed 30th Jan 2026).

Created: 30 Jan 2026, 10:27 a.m. | Last Modified: 30 Jan 2026, 10:54 a.m.

Panel Version: 8.99

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual developmental disorder, autosomal dominant 66, OMIM:619910

Publications

• 33057194
• 35358416
• 40834682

I don't know

Recent publication Zhu et al 2025 PMID: 40834682: ATP2B1 variants associated with generalized epilepsy without neurodevelopmental disorders and the underlying mechanism.

ATP2B1 variants were identified in five individuals affected by generalized epilepsy or genetic epilepsy with febrile seizures plus from two unrelated families. The identified ATP2B1 variants included one de novo heterozygous missense variant (c.2920A>G/p.Ile974Val) and one co-segregated heterozygous missense variant (c.76G>A/p.Asp26Asn). The de novo variant was absent in any public population database and the co-segregated variant had an extremely low minor allele frequency (MAF = 7.955×10-6) in gnomAD.

All of the patients had favourable outcomes without neurodevelopmental disorders. Missense variants located in the functional domain with severe damaging effect were more likely to manifest as neurodevelopmental disorders comorbid with epilepsy. ATP2B1 exhibits relatively low baseline expression at early development stages but significantly increases in later stages, with particularly high expression in the striatum, which is consistent with the generalized epilepsy phenotype observed in this study, and explains that severe damage variants were associated with early-onset neurodevelopmental disorders, whereas milder damage variants were associated with epilepsy.

Created: 16 Dec 2025, 3:35 p.m. | Last Modified: 16 Dec 2025, 3:35 p.m.

Panel Version: 8.77

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
generalized epilepsy

Publications

• PMID: 40834682

I don't know

New gene added by Konstantinos Varvagiannis based on paper Rahimi et al (2022 - PMID: 35358416) who describes 12 unrelated individuals with monoallelic ATP2B1 variants.
Seizures seen in 6/12 infantile spasms and a febrile seizure has been included in this classification.
ATP2B1 rated Green on ID. Due to lack of clinical information and incomplete seizure phenotype in all individuals rating Amber with watchlist tag.

Created: 2 Aug 2022, 4:13 p.m. | Last Modified: 2 Aug 2022, 4:13 p.m.

Panel Version: 2.551

I don't know

At least 12 individuals with NDD due to monoallelic missense/pLoF ATP2B1 variants have been reported to date. Seizures were observed in 5 of them.

Currently there is no associated phenotype in OMIM, G2P, SysID, PanelApp Australia.

Based also on the evidence discussed below, please consider inclusion with amber rating.
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Rahimi et al (2022 - PMID: 35358416) describe 12 unrelated individuals with monoallelic ATP2B1 variants.

Phenotype consisted of DD (12/12), ID [9/12 - mild or less commonly moderate, with 3 additional subjects "unclassified" likely due to their age (#6: 3y nonverbal/nonambulatory, could sit and roll / #8: 3y, sitting at 1y, 1st words:26m / #12: at 5y nonambulatory/nonverbal)]. Behavioral issues were observed in 8/11 (ASD in 5/11). Seizures were reported in 5/12 (one further had abnormal EEG). Minor features - albeit not consistent/without recognizable gestalt - were reported in 6. Anomalies of digits and marfanoid habitus were reported in 4 and 2.

All subjects were investigated by singleton/trio exome sequencing.

Previous investigations incl. karyotype, CMA, analysis of individual genes (e.g. FMR1, ZEB2) or metabolic workup were normal for several individuals with one having a concurrent diagnosis of mosaic (20%) XXY and another harboring an additional hmz variant for a liver disorder.

9 different missense and 3 nonsense ATP2B1 variants were identified, shown to have occurred de novo in all cases where parental samples were available (9/12).

ATPase plasma membrane Ca+2 transporting 1, the protein encoded by ATP2B1, is an ATP-driven calmodulin-dependent Ca+2 pump which removes intracellular calcium from the cytosol. As the authors comment calcium pumps are thought to have a crucial role on neuronal function.

All variants identified were absent from gnomAD with the exception of c.2365C>T / p.Arg789Cys (de novo) which is present once in the database. ATP2B1 has a pLI of 1 and a missense Z-score of 5.29.

The variants affected several ATP2B1 isoforms. Variants were reported using NM_001001323.2, corresponding to ATP2B1a isoform which is mainly detected in brain (as also in GTEx).

In silico predictions were in favor of a deleterious effect and structural modeling supported the role of the affected residues.

The nonsense variants occurred in positions predicted to lead to NMD (not studied).

Transfection of an ATP2B1-yellow fluorescent protein (YFP) expression plasmid for wt or variants in HEK293 cells, revealed membranous fluorescence for wt, significantly altered localization for 3 variants (Asp239Gly, Thr264Ile, Arg991Gln), shift to cytoplasmic localization for 4 others (Thr425Lys, Arg763Pro, Glu824Lys, Gln857Arg) with statistically non-significant effect for 2 others (His459Arg and Arg789Cys).

Fluorometric [Ca+2]i analysis in HEK293 cells expressing wt or variant ATP2B1 revealed that all missense variants affected Ca+2 transport. This was not the case for wt ATP2B1 or for another missense variant used as control (drawn from gnomAD).

Of note, a further (13th) affected individual with another missense variant (c.1793T>C / p.Ile598Thr) was excluded from the phenotypic analysis. The membrane localization and Ca+2 transport did not appear to be affected by this variant which was classified as VUS although it a different impact from those studied.

Overall loss-of-function is thought to be the underlying mechanism based on the above (and supported by few reported cases with gross deletions spanning also ATP2B1). A dominant negative effect for missense variants (affecting heteromeric complex formation with neuroplastin or basigin) could not be completely excluded, but not supported either by the localization of the identified variants.

In the supplement the authors include 3 DDD study participants previously reported to harbor de novo pLoF/missense variants though with few available clinical information (PMID: 33057194 - DDD13k.05076 : c.2883del / DDD13k.04028 : c2512A>C - p.Ile838Val / DDD13k.08944 : c.2129A>C - p.Asp710Ala).

The authors discuss on the role of ATP2B1 on Ca+2 homeostasis in the CNS and neurodevelopment overall (also based on isoform expression in rat brain).
Sources: Literature

Created: 2 Apr 2022, 1:19 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Seizures; Abnormality of head or neck

Publications

• 35358416
• 33057194