Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000182351 | SCV000234664 | likely pathogenic | not provided | 2014-08-20 | criteria provided, single submitter | clinical testing | p.Glu84Asp (GAG>GAC): c.252 G>C in exon 1 of the LMNA gene (NM_170707.2). Mutations in the LMNA gene have been reported in up to 10% of patients with autosomal dominant familial dilated cardiomyopathy with conduction defects (Muschke P et al., 2007) and have been associated with several disorders of striated muscle, nerve, adipose, and vascular tissue, collectively referred to as the laminopathies (Hershberger R et al., 2009). An E84D variant that is likely pathogenic was identified in the LMNA gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The E84D variant was not observed in approximately 6,500 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 E84D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, 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 the same residue (E84K) and at nearby residues (E82K, L85R) have been reported in association with cardiomyopathy, supporting the functional importance of this residue and region of the protein.Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in CARDIOMYOPATHY panel(s). |
| Invitae | RCV001852311 | SCV002150749 | uncertain significance | Charcot-Marie-Tooth disease type 2 | 2021-09-23 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 200929). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 84 of the LMNA protein (p.Glu84Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. |