Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000522208 | SCV000622080 | uncertain significance | not provided | 2018-07-24 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the LAMA4 gene. The F1266L variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). However, the F1266L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to phenylalanine (F) are tolerated across species and where leucine (L) is present as the wild type in several species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. |
| Invitae | RCV002527656 | SCV003471671 | uncertain significance | Dilated cardiomyopathy 1JJ | 2022-07-26 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1266 of the LAMA4 protein (p.Phe1266Leu). This variant is present in population databases (rs138232283, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with LAMA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 453203). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. |
| Ambry Genetics | RCV003159699 | SCV003910267 | uncertain significance | Cardiovascular phenotype | 2022-11-19 | criteria provided, single submitter | clinical testing | The p.F1266L variant (also known as c.3798C>A), located in coding exon 27 of the LAMA4 gene, results from a C to A substitution at nucleotide position 3798. The phenylalanine at codon 1266 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. 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. |