Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Mayo Clinic Laboratories, |
RCV000057219 | SCV001715571 | likely pathogenic | not provided | 2020-11-02 | criteria provided, single submitter | clinical testing | PM5, PM2, PM6_supporting, PP3 |
Invitae | RCV001854172 | SCV002262706 | pathogenic | Charcot-Marie-Tooth disease type 2 | 2023-08-10 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 66763). This missense change has been observed in individuals with arrythmogenic right ventricular cardiomyopathy (PMID: 15219508; Invitae). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 349 of the LMNA protein (p.Arg349Leu). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg349 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18035086, 22700598, 23349452, 24080738, 28620495, 28641778). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. |
Ambry Genetics | RCV003343625 | SCV004074698 | uncertain significance | Cardiovascular phenotype | 2023-08-22 | criteria provided, single submitter | clinical testing | The p.R349L variant (also known as c.1046G>T), located in coding exon 6 of the LMNA gene, results from a G to T substitution at nucleotide position 1046. The arginine at codon 349 is replaced by leucine, an amino acid with dissimilar properties. This variant has been detected in a mother and identical twins with dilated cardiomyopathy (Hermida-Prieto M et al. Am J Cardiol, 2004 Jul;94:50-4). In vitro analysis suggested that this variant may result in protein aggregation in C2C12 myoblast overexpression studies; however, additional evidence is needed to confirm this finding (Anderson CL et al. NPJ Genom Med, 2021 Dec;6:103). Another alteration at the same codon, p.R349W (c.1045C>T), has been reported in association with laminopathy phenotypes (van Tintelen JP et al. Am Heart J. 2007 Dec;154(6):1130-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Epithelial Biology; Institute of Medical Biology, |
RCV000057219 | SCV000088332 | not provided | not provided | no assertion provided | not provided |