Submissions for variant NM_014874.3(MFN2):c.653T>C (p.Leu218Pro) (rs879253925)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236657	SCV000292831	uncertain significance	not provided	2016-02-25	criteria provided, single submitter	clinical testing	The L218P variant has been previously reported as probably disease causing; however, information about the patient's phenotype and segregation analysis was not provided (Østern et al., 2013). Missense variants in nearby residues (I213T, D214N, F216S, F223L) have been reported in the Human Gene Mutation Database in association with axonal neuropathy or CMT2A (Stenson et al., 2014), supporting the functional importance of this region of the protein. L218P 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 L218P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant.
Molecular Diagnostics Laboratory, M Health: University of Minnesota	RCV000761252	SCV000891209	likely pathogenic	Charcot-Marie-Tooth disease, type 2A2A	2018-06-04	criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV000789064	SCV000928413	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only