Cerebral vascular malformations

Gene: ANO1

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 10 Dec 2025, 2:36 p.m. | Last Modified: 10 Dec 2025, 2:36 p.m.

Panel Version: 4.9

Reviewing again PMID: 37253099 Pinard et al 2023

7 missense variants in ANO1 were identified in probands from 8 families with Moyamoya disease (MMD). Cohort was 84 initial families from the University of Texas Health centre with a further 24 probands from Yale, and126 probands from France.

ANO1 encodes anoctamin-1, a calcium-activated chloride channel (CaCC). Wild-type and mutant channels were expressed in HEK293T cells and channel function assessed using patch-clamp techniques.

Gain of function - more linearized and increased current-voltage relationship
p.Met658Val - segregated with MMD in two families (MM001 and MM137) who were found to be distantly related, not present in gnomAD
p.Glu459Lys in family MM184 - heterozygous in proband, not present in gnomAD - no segregation data
p.Thr740Ile in family Baylor2 - heterozygous in proband, not present in gnomAD - no segregation data
p.Glu170Lys in family Baylor1 (similar current to wild type, but significantly increased Ca2+ sensitivity, table 1 says GOF) - homozygous in the proband, unaffected consanguineous parents, found in gnomAD in 23 exomes and 1 genome - no segregation data

Loss of function - did not have identifiable CaCC current
p.Arg890Gln in family M117 - heterozygous in proband, found in gnomAD in 78 exomes, and 10 genomes - no segregation data

3 variants with functional data similar to wild type
p.Arg77Gln in family MM035 - heterozygous in proband, found in gnomAD in 8 exomes, and 18 genomes, heterozygous mother and daughter are unaffected
p.Ser196Thr in family MM153 - heterozygous in proband, found in gnomAD in 1 exome, heterozygous unaffected mother

Another paper PMID:37012328 - Zanoni et al 2023 analysed 88 paediatric Moyamoya Angiopathy patients with ANO1 on their panel but did not report any pathogenic variants found.

Summary: quite a confusing picture of missense variants all reported in one paper. 3 cases with heterozygous rare variants, 1 with segregation data and 1 homozygous case with unaffected parents with functional evidence to supports a gain of function mechanism, An addition case with a loss of function variant also reported, as are two variants with function similar to wild type.

Created: 11 Jun 2025, 9:26 p.m. | Last Modified: 11 Jun 2025, 9:26 p.m.

Panel Version: 4.4

Green List (high evidence)

Three ANO1 variant have been associated with Moyamoya disease 7 (OMIM:620687) in three unrelated cases (PMID: 37253099). Two of the variants were heterozygous in the patients, while the third was homozygous. For each of the variants, electrophysiologic studies in variant transfected HEK293 cells revealed that the variant channel had an increased Ca(2+) sensitivity resulting in increased membrane Cl- conductance at lower intracellular Ca(2+) levels in comparison to the controls, which is consistent with a gain-of-function effect.

Created: 8 Apr 2025, 3:29 p.m. | Last Modified: 8 Apr 2025, 3:29 p.m.

Panel Version: 3.22

Comment on publications: PMID: 37012328 was not relevant to this gene

Created: 8 Apr 2025, 3:18 p.m. | Last Modified: 8 Apr 2025, 3:18 p.m.

Panel Version: 3.22

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 37253099

I don't know

37253099: 6 families showed AD, 1 patient AR. GOF and LOF implied. 7 variants identified total from 84 unsolved families and additional 150 probands. In vitro modelling of different missense variants in HEK cells shows GOF and LOF mechanisms. GOF variants (p.Met658Val, p.Glu459Lys, p.Thr740Ile p.Glu170Lys) have increased membrane Cl− conductance at lower intracellular Ca2+ levels, determined through patch clamp. Predicted LOF p.Arg890Gln (in gnomAD) as no Ca2+ currents evoked. Some variants show no alteration to Ca2+ sensitivity (p.Arg77Gln [in gnomAD) and p.Ser196Thr) but near binding site for PIP2. Authors note that ANO1 may be paternally imprinted as affected individuals who inherited the variant from their mothers had an earlier age at onset, whereas those who inherited the variant from their father had later onset (families MM137/MM001).
37012328: 88 paediatric MMA patients, 3 patients with mixed clinical presentations had ANO1 variants through WES filtering, no evidence of pathogenicity provided.
Sources: Literature

Created: 4 Apr 2025, 12:11 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Moyamoya disease 7, 620687

Publications

• 37253099
• 37012328

Mode of pathogenicity
Other