Clefting

Gene: AMOTL1

Comment on phenotypes: This gene has been associated with relevant phenotypes in OMIM (MIM #621192) and the OMIM record was last accessed on 18 December 2025.

Created: 18 Dec 2025, 9:33 p.m. | Last Modified: 18 Dec 2025, 9:33 p.m.

Panel Version: 6.19

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 2 May 2024, 11:59 a.m. | Last Modified: 2 May 2024, 11:59 a.m.

Panel Version: 5.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Comment on list classification: There is now sufficient evidence to rate this gene as Green at the next GMS panel update.

At least 16 individuals from 12 families have been identified with heterozygous variants in a AMOTL1 hotspot (PMIDs: 30375152; 33026150; 36751037). The most common clinical features were orofacial clefting (15/16; 94%), large and dysplastic ears (10/16; 62.5%), congenital heart disease (8/16; 50%), tall stature (7/16; 44%), hearing loss (5/16; 31%), liver disease (5/16; 31%), and neurodevelopmental disease (5/16; 31%).

Created: 24 Jul 2023, 12:57 p.m. | Last Modified: 24 Jul 2023, 12:57 p.m.

Panel Version: 4.79

Green List (high evidence)

PMID: 36751037 - this cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157–161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.

Created: 11 Jul 2023, 8:26 a.m. | Last Modified: 11 Jul 2023, 8:26 a.m.

Panel Version: 4.78

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
orofacial clefting; cardiac anomalies; tall stature

Publications

• PMID: 36751037

Mode of pathogenicity
Other

Red List (low evidence)

Comment on list classification: Promoting this gene from grey to red. 2 cases but mouse model does not recapitulate the phenotype.

Created: 19 Jan 2021, 10:53 p.m. | Last Modified: 19 Jan 2021, 10:53 p.m.

Panel Version: 2.18

As outlined by expert reviewer 2 cases reported. Mouse model did not support phenotype.

PMID: 33026150 - Rips et al 2020 - report a a female infant from consanguineous parents with cleft lip and palate, imperforate anus and dysmorphic features. Exome sequencing of the child and parents identified a de novo variant in AMOTL1 (c.479C>T; p.Pro160Leu). An additional homozygous deletion/insertion variant in F12 (c.971_1018+24del) was detected which has been previously linked to autosomal dominant hereditary angioedema. This was considered a secondary finding.

PMID:30375152 - Liegel et al 2019 - describe a child with cleft palate, ventricular septal defect and double orifice mitral value, and advanced bone age. The father also was born with a cleft lip and palate, and an atrial septal defect and a reported mitral valve abnormality. Through trio exome sequencing a variant in AMOTL1 was identified c.469C>T; p.Arg157Cys. It is thought to have arisen de novo in the father and was passed to the son. The variant was absent from ExAC and gnomAD. Using mouse models, they found that the Amotl1 R157C missense variant significantly reduces viability of mice but they did not see evidence of cleft palate or heart defects.

Created: 19 Jan 2021, 10:51 p.m. | Last Modified: 19 Jan 2021, 10:51 p.m.

Panel Version: 2.15

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

Phenotypes
cleft lip/palate MONDO:0016044

Publications

• 33026150
• 30375152

Red List (low evidence)

Two unrelated families reported. In one, the variant was identified in parent and child who had orofacial cleft and cardiac abnormalities. Second report in PMID 33026150, de novo missense variant and cleft lip/palate, imperforate anus and dysmorphism. Mouse model does not recapitulate phenotype.
Sources: Literature

Created: 3 Nov 2020, 11:21 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cleft lip and palate; imperforate anus; dysmorphism

Publications

• 33026150