rs371830740

Description

The P323L variant of uncertain significance in the FLNA gene has not been published as pathogenic or been reported as benign in a peer reviewed journal to our knowledge. This variant is observed in 4/90,069 (0.004%) European (non-Finnish) alleles, including one hemizygous individual, in large population cohorts (Lek et al., 2016). The P323L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 323 of the FLNA protein (p.Pro323Leu). This variant is present in population databases (rs371830740, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with FLNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 387722). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FLNA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.