Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000235905 | SCV000293691 | uncertain significance | not provided | 2015-12-13 | criteria provided, single submitter | clinical testing | The A375T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A375T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A375T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. |
| Invitae | RCV001038975 | SCV001202480 | uncertain significance | Charcot-Marie-Tooth disease type 2 | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 375 of the LMNA protein (p.Ala375Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 246226). 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 expected to disrupt LMNA protein function with a positive predictive value of 95%. 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. |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV001256917 | SCV001433435 | uncertain significance | Dilated cardiomyopathy 1A | 2020-03-26 | criteria provided, single submitter | clinical testing |