Submissions for variant NM_014874.3(MFN2):c.1150C>T (p.Arg384Trp) (rs777353788)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235909	SCV000293093	uncertain significance	not provided	2015-08-26	criteria provided, single submitter	clinical testing	The R384W variant has previously been reported in a single individual with moderate axonal and demyelinating sensorimotor neuropathy with normal MRI of the optic nerve and normal visual evoked potential (Auranen et al., 2013). It is unclear if this variant segregates with disease in this family; this individual's unaffected father did not harbor the R384W variant, but the unaffected mother was not evaluated for this variant (Auranen et al., 2013). The R384W 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.The R384W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (M376V/T/R/I, S378P, A382P, A383V, C390R/F) have been reported in the Human Gene Mutation Database in association with Charcot-Marie Tooth neuropathy type 2 or early onset axonal neuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Inherited Neuropathy Consortium	RCV000789365	SCV000928720	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only