Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001050654 | SCV001214773 | uncertain significance | Charcot-Marie-Tooth disease type 2 | 2024-06-11 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 275 of the MFN2 protein (p.Arg275Trp). This variant is present in population databases (rs368499636, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 36964972). ClinVar contains an entry for this variant (Variation ID: 444157). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MFN2 protein function. 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. |
| Ambry Genetics | RCV002431472 | SCV002681851 | uncertain significance | Inborn genetic diseases | 2022-07-15 | criteria provided, single submitter | clinical testing | The p.R275W variant (also known as c.823C>T), located in coding exon 7 of the MFN2 gene, results from a C to T substitution at nucleotide position 823. The arginine at codon 275 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003993991 | SCV004813061 | uncertain significance | not specified | 2024-02-12 | criteria provided, single submitter | clinical testing | Variant summary: MFN2 c.823C>T (p.Arg275Trp) results in a non-conservative amino acid change located in the Dynamin-type guanine nucleotide-binding (G) domain (IPR030381) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250200 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.823C>T has been reported in the literature in at least one heterozygous individual affected with Charcot-Marie-Tooth Disease, Axonal, Type 2A2A, Autosomal Dominant. These data do not provide sufficient evidence to allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36964972). ClinVar contains an entry for this variant (Variation ID: 444157). Based on the evidence outlined above, the variant was classified as uncertain significance. |