Early onset or syndromic epilepsy

Gene: LAMC3

Green List (high evidence)

Comment on list classification: There is sufficient evidence available (six unrelated cases) for the association of biallelic LAMC3 variants with seizures. The 'Disputed' rating in ClinGen is only relevant to monoallelic MOI. Hence, this gene should be promoted to green rating with biallelic MOI in the next GMS update.

Created: 21 Oct 2025, 1:29 p.m. | Last Modified: 23 Oct 2025, 11:49 a.m.

Panel Version: 8.57

There are seven unrelated families reported with biallelic variants (either homozygous or compound heterozygous) in LAMC3 and cortical malformations. Childhood-onset seizures is the most common clinical manifestation that is reported in all patients except the foetal case.

Biallelic LAMC3 variants are associated with relevant phenotypes in OMIM (MIM #614115, record accessed on 21 October 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel). This gene has also been rated green with biallelic MOI on Genetic epilepsy panel in PanelApp Australia (https://panelapp-aus.org/panels/202/gene/LAMC3/) Biallelic LAMC3 variants are not yet associated with any relevant phenotypes in ClinGen.

Monoallelic LAMC3 variants are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism expert panel in ClinGen (https://search.clinicalgenome.org/CCID:005265)

This was based on the following evidence:
Although over 25 unique variants have been reported in humans, autism spectrum disorder was the primary ascertainment for the largest number of individuals. Variants have also been reported in probands with intellectual disability and/or developmental delay. However, the variants were primarily identified in individuals with limited phenotype data from large cohort studies, and none had experimental evidence of gene impact (PMIDs: 21572417, 23160955, 27525107, 28191889, 28965761, 30564305, 31398340).
Sources: Literature

Created: 21 Oct 2025, 12:37 p.m. | Last Modified: 21 Oct 2025, 1:26 p.m.

Panel Version: 8.48

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cortical malformations, occipital, OMIM:614115; occipital pachygyria and polymicrogyria, MONDO:0013583

Publications

• 21572413
• 26802095
• 29247375
• 33639934
• 34354730