Submissions for variant NM_014874.3(MFN2):c.818T>G (p.Val273Gly) (rs1458700065)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519202	SCV000617756	likely pathogenic	not provided	2017-07-10	criteria provided, single submitter	clinical testing	The V273G variant has been previously reported to segregate with disease in multiple affected individuals from a single large family with CMT (Lawson et al., 2005). The V273G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a conserved position within the dynamin type G domain of the MFN2 protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae	RCV000689677	SCV000817340	uncertain significance	Charcot-Marie-Tooth disease, type 2	2019-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine with glycine at codon 273 of the MFN2 protein (p.Val273Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Charcot-Marie-Tooth disease (CMT) in a large family (PMID: 16043786). ClinVar contains an entry for this variant (Variation ID: 449524). Experimental studies have shown that this missense change does not affect mitofusin expression, mitochondrial morphology, ultrastructure, mtDNA content, and respiratory capacity in fibroblasts (PMID: 18316077). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Inherited Neuropathy Consortium	RCV000789395	SCV000928750	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only

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