Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000195514 | SCV000251711 | likely pathogenic | not provided | 2014-03-11 | criteria provided, single submitter | clinical testing | p.His242Arg (CAC>CGC): c.725 A>G in exon 8 of the MFN2 gene (NM_014874.3). The H242R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H242R variant 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. The H242R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar 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 (T232A, T232N, L233V, T236M, F240I, V244M, L248V, S249F, R250W, R250Q, P251A) have been reported in association with Charcot-Marie-Tooth disease, type 2A2, supporting the functional importance of this 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 MITONUC-MITOP panel(s). |
| Invitae | RCV000690762 | SCV000818488 | uncertain significance | Charcot-Marie-Tooth disease, type 2 | 2020-01-24 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine with arginine at codon 242 of the MFN2 protein (p.His242Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MFN2-related disease. ClinVar contains an entry for this variant (Variation ID: 214641). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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. |
| Genesis Genome Database | RCV000857099 | SCV000999672 | uncertain significance | Charcot-Marie-Tooth disease | 2019-08-14 | no assertion criteria provided | research |