Ataxia and cerebellar anomalies - narrow panel

Gene: ATP2B2

Green List (high evidence)

Comment on list classification: As there is sufficient evidence available for the association of monoallelic ATP2B2 variants with childhood-onset ataxia (nine families), this gene can be promoted to green rating in the next GMS update.

Created: 29 Jul 2026, 11:02 a.m. | Last Modified: 29 Jul 2026, 11:10 a.m.

Panel Version: 9.18

PMID:29655659 (2018) reported a novel missense variant (p.Val1143Phe) in PMCA2/ ATP2B2 gene in a 27-year old male patient presenting with congenital cerebellar ataxia but with no overt signs of deafness. This patient presented with delayed motor development requesting clinical attention at age 5 months, had dysmetria and intentional tremor at age 3 and showed obvious gait ataxia at age 4. The patient was also reported with impaired speech and moderate intellectual disability. Brain MRI studies revealed global cerebellar atrophy without cortical and brainstem involvement.

PMID:37675773 (2023) reported seven individuals with rare, predicted deleterious heterozygous ATP2B2 variants, including 5 missense substitutions and 2 frameshift variants. De novo status was confirmed for six of these variants. All individuals displayed a spectrum of neurological abnormalities ranging from ataxia (5/7 patients) and other movement disorders including dystonic features (3 patients) to complex neurodevelopmental manifestations with intellectual disability, global developmental delay, and seizures (6 patients). Two cases with recurrent amino-acid variation showed distinctive overlap with cerebellar atrophy-associated ataxia and epilepsy. In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects.

PMID:39367743 (2025) reported six previously unreported patients from five unrelated families with four different missense variants and one frameshift variant (p.Leu1089GlnfsTer60). All missense variants were confirmed de novo, while the frameshift variant is paternally inherited in one and of unknown inheritance in other. These patients shared phenotypic features with the previously described patients including developmental delay and intellectual disability (all six patients), cognitive disturbances, autistic features epilepsy (3 patients), ataxia (3 patients) and other movement disorders (one patient). Striking cerebellar atrophy was observed in one affected individual.

In total, there are 13 patients (from 12 families) with (global) developmental delay/ intellectual disability, 9 patients (from eight families) with seizures, 9 patients (from nine families) with ataxia and 4 patients (from four families) reported with other movement disorders including dystonia.

This gene has been associated with hearing loss in both OMIM (MIM #619804, last accessed 29 July 2026) and ClinGen ('Definitive' rating for autosomal dominant nonsyndromic hearing loss (MONDO:0019587) by Hearing Loss GCEP), but not with the neurological/ neurodevelopmental phenotypes in these resources.

Created: 29 Jul 2026, 10:57 a.m. | Last Modified: 29 Jul 2026, 10:57 a.m.

Panel Version: 9.13

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
neurodevelopmental disorder, MONDO:0700092; cerebellar ataxia, MONDO:0000437; epilepsy, MONDO:0005027; intellectual disability,MONDO:0001071; inherited dystonia, MONDO:0044807

Publications

• 29655659
• 37675773
• 39367743

Mode of pathogenicity
Other

Green List (high evidence)

ATP2B2 is associated with Deafness, autosomal dominant 82 (OMIM 619804) in OMIM. Emerging evidence suggests that heterozygous pathogenic variants in ATP2B2 can cause a neurodevelopmental phenotype.

Recent papers have outlined and extended neurodevelopmental phenotype (PMID: 39367743, PMID: 37675773, PMID: 29655659) not documented in OMIM or G2P. Summarised phenotypes from 14 reported individuals (13 unrelated individuals) - Global developmental delay (12/14), delayed motor development (12/14), ataxia (9/14), impaired speech (13/14), intellectual disability (13/14), cerebellar atrophy (4/14), behavioural issues (9/14), seizures (9/14), hypotonia (6/14), dysmorphic features (4/14), hearing abnormalities (3/14), and ophthalmological abnormalities (6/14).

PMID: 29655659 - Heterozygous missense. Targeted NGS, unknown inheritance.

PMID: 37675773 - Trio exome sequencing for families 1-6, confirmed de novo status for all 6 families. Seventh family could not be confirmed. 5 missense variants, 2 frameshift variants.

PMID: 39367743 - Trio exome sequencing for families 1-4, confirmed de novo in all 4 families. One case paternally inherited, one unknown. 4 missense variants, 1 frameshift variant (2 individuals in the same family).

ATP2B2 is plasma membrane Ca2+ ATPase involved in Ca2+ homeostasis. Ca2+ deregulation in humans and mice can cause cognitive, behavioural, sensory, and movement disorders. Discussed in detail in PMID: 37675773.

Request addition to R27, R29, R55, R59, R69, R84, Ataxia and Cerebellar Anomalies - Narrow Panel.
Sources: Expert Review

Created: 24 Jun 2026, 2:30 p.m.

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

Phenotypes
Global Developmental Delay; Delayed Motor Development; Ataxia; Impaired Speech; Intellectual Disability; Cerebellar Atrophy; Behavioural Issues; Seizures; Hypotonia; Dysmorphic Features; Hearing Abnormalities; Ophthalmological Abnormalities

Publications

• PMID: 29655659
• 37675773
• 39367743

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