Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000156060 | SCV000205773 | pathogenic | Primary dilated cardiomyopathy | 2013-09-06 | criteria provided, single submitter | clinical testing | The Glu82Lys variant in LMNA has been reported in at least 2 families with DCM a nd conduction system abnormalities, and segregated with disease in 8 affected re latives (Wang 2006, Wu 2010). It has not been identified in large population stu dies. Functional studies (in vitro) suggest an effect on protein function and mi ce carrying the variant exhibited clinical features of DCM (Wang 2006, Lu 2010, Sun 2010). In summary, this variant meets our criteria to be classified as patho genic (http://pcpgm.partners.org/LMM) based upon segregation studies, absence fr om controls, and functional evidence. |
Gene |
RCV000057380 | SCV000292778 | pathogenic | not provided | 2015-03-30 | criteria provided, single submitter | clinical testing | The E82K mutation was reported to segregate with DCM and atrial ventricular block in eight individuals from two Chinese families (Wang et al., 2006; Wu et al., 2010). E82K 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. In vitro studies showed E82K significantly reduced expression and altered localization of connexin 43 (Sun et al., 2010). Studies in transgenic mice showed E82K activates the FAS and mitochondrial pathways of apoptosis in heart tissue (Lu et al., 2010). E82K 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 across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (R72L, R72C, L85R, R89L) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. |
Invitae | RCV000457442 | SCV000548860 | pathogenic | Charcot-Marie-Tooth disease type 2 | 2023-05-27 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 20497714, 21151901). 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: 66882). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) and atrioventricular (AV) block (PMID: 16630578, 20155465). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 82 of the LMNA protein (p.Glu82Lys). |
Epithelial Biology; Institute of Medical Biology, |
RCV000057380 | SCV000088493 | not provided | not provided | no assertion provided | not provided |