Submissions for variant NM_014874.3(MFN2):c.1987C>T (p.Arg663Cys) (rs369762154)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197786	SCV000251721	uncertain significance	not provided	2018-07-16	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MFN2 gene. The R663C variant in the MFN2 gene has been previously reported in a pediatric patient with an atypical phenotype including acute neurological failure and deafness; the variant was also identified in his mother who was reported to have a toe-walking gait (DiMeglio et al., 2015). The R663C variant is observed in 20/10150 (0.2%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). The R663C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense mutations in nearby residues have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth 2A (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001087905	SCV000657719	likely benign	Charcot-Marie-Tooth disease, type 2	2019-12-31	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001101761	SCV001258398	uncertain significance	Hereditary motor and sensory neuropathy with optic atrophy	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV001087905	SCV001258399	benign	Charcot-Marie-Tooth disease, type 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.