rs782066542

Description

The p.M424V variant (also known as c.1270A>G), located in coding exon 8 of the FLNA gene, results from an A to G substitution at nucleotide position 1270. The methionine at codon 424 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 424 of the FLNA protein (p.Met424Val). This variant is present in population databases (rs782066542, gnomAD 0.02%). 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: 588806). 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.

Has not been previously published as pathogenic or benign to our knowledge; Observed in 3/180189 (0.0017%) alleles in large population cohorts, and has been observed in the hemizygous state in multiple unrelated adult individuals tested at GeneDx and in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function