Submissions for variant NM_014874.3(MFN2):c.775C>T (p.Arg259Cys) (rs587777875)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197364	SCV000251712	likely pathogenic	not provided	2017-11-28	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the MFN2 gene. The R259C variant has been previously reported in multiple individuals with CMT2A (Sitarz et al., 2012; Drew et al., 2015; Leonardi et al., 2015). TheR259C variant is not observed in large population cohorts (Lek et al., 2016). The R259C variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, missense variants in a nearby residue (S263P) and at the sameresidue (R259L/H) have been reported in the Human Gene Mutation Database in association with MFN2-related neuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Athena Diagnostics Inc	RCV000197364	SCV000614094	likely pathogenic	not provided	2017-02-16	criteria provided, single submitter	clinical testing
Invitae	RCV000653884	SCV000775774	pathogenic	Charcot-Marie-Tooth disease, type 2	2019-08-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 259 of the MFN2 protein (p.Arg259Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Charcot-Marie-Tooth disease (PMID: 22492563, 24957169, 25802885, 25957633). ClinVar contains an entry for this variant (Variation ID: 155730). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Different missense substitutions at this codon (p.Arg259Leu and p.Arg259His), including one determined to be likely pathogenic, have been reported in individuals affected with Charcot-Marie-Tooth disease (PMID: 19350291, 24627108, 24863639). This suggests that the arginine residue is critical for MFN2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory,London Health Sciences Centre	RCV000789066	SCV001336795	likely pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Northcott Neuroscience Laboratory, ANZAC Research Institute	RCV000143799	SCV000188692	pathogenic	Charcot-Marie-Tooth disease, type 2A2A		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Inherited Neuropathy Consortium	RCV000789066	SCV000928415	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only