Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000482327 | SCV000568774 | likely pathogenic | not provided | 2016-02-08 | criteria provided, single submitter | clinical testing | The H277R variant has previously been reported in association with autosomal dominant Charcot-Marie-Tooth neuropathy type 2 (CMT2) in two related patients who had age of onset at 10 and 15 years of age (Verhoeven et al., 2006). The H277R 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. This substitution occurs at a position that is conserved across species and this position is predicted to be within the GTPase domain of the MFN2 protein, where many pathogenic variants cluster (Choi et al., 2015). Missense variants in nearby residues (V273G, R274Q, Q276R/H, R280H) have been reported in the Human Gene Mutation Database in association with CMT2 (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, the H277R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Inherited Neuropathy Consortium | RCV000789406 | SCV000928761 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |