Submissions for variant NM_014874.3(MFN2):c.647T>C (p.Phe216Ser) (rs387906990)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235670	SCV000292875	pathogenic	not provided	2015-05-18	criteria provided, single submitter	clinical testing	The F216S variant has been previously reported as a homozygous variant in a patient with early onset hereditary motor and sensory neuropathy; the parents were unaffected carriers of the F216S variant, suggesting autosomal recessive inheritance (Vallat et al., 2008). F216S was subsequently reported in two siblings with early onset CMT2 who both had a second MFN2 variant on the opposite allele; the mother was an unaffected carrier of the F216S variant (Polke et al., 2011). F216S 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. It is a non-conservative amino acid substitution that occurs at a highly conserved position in the protein. Missense variant in nearby residues (T206I, I213T, D214N, F223L) have been reported in the Human Gene Mutation Database in association with neuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Invitae	RCV000456775	SCV000547927	likely pathogenic	Charcot-Marie-Tooth disease, type 2	2018-04-24	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine with serine at codon 216 of the MFN2 protein (p.Phe216Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases at a very low frequency (rs387906990, ExAC <0.01%). This variant has been observed in the homozygous state or on the opposite chromosome (in trans) from a pathogenic variant in multiple individuals affected with CMT2 (PMID: 18957892, 21715711, 23147504). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 30736). 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 tolerated, but these predictions have not been confirmed by published functional studies. This missense change is located within a functionally conserved GTPase domain of the MFN2 protein (PMID: 19812251) in close proximity to several previously reported MFN2 missense mutations (PMID: 15549395, 16043786, 18458227, 23733358, 26801520). These observations suggest that missense substitutions within this domain may affect protein function, but experiments have not been done to test this possibility for the p.Phe216Ser variant. For these reasons, this variant has been classified as Likely Pathogenic.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000235670	SCV000610391	pathogenic	not provided	2017-02-22	criteria provided, single submitter	clinical testing
OMIM	RCV000023714	SCV000045005	pathogenic	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2A2B	2011-07-12	no assertion criteria provided	literature only