Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genetic Services Laboratory, |
RCV000145899 | SCV000193036 | pathogenic | Myopathy, centronuclear | 2013-02-08 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000641108 | SCV000762730 | pathogenic | Charcot-Marie-Tooth disease, dominant intermediate B | 2018-08-13 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with tryptophan at codon 369 of the DNM2 protein (p.Arg369Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with centronuclear myopathy (CNM) in several families (PMID: 16227997, 22613877). This variant has also been reported in individuals with CNM and cardiomyopathy (PMID: 25492887) as well as CNM with paravertebral muscles hypertrophy and mild neutropenia (PMID: 20817456). ClinVar contains an entry for this variant (Variation ID: 7280). Experimental studies have shown that this missense change leads to abnormally stable polymers and cytosolic aggregates (PMID: 24016602, 20529869). A mouse model for CNM carrying this missense change shows reduced de novo actin filament formation, increased cytosolic aggregates and impaired actin dependent trafficking (PMID: 28676641). A different missense substitution at this codon (p.Arg369Gln) has been determined to be pathogenic (PMID: 16227997, 25501959). This suggests that the arginine residue is critical for DNM2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000007703 | SCV000027904 | pathogenic | Myopathy, centronuclear, 1 | 2005-11-01 | no assertion criteria provided | literature only |