Submissions for variant NM_014874.3(MFN2):c.2219G>C (p.Trp740Ser) (rs28940292)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197403	SCV000253917	pathogenic	Charcot-Marie-Tooth disease, type 2	2020-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan with serine at codon 740 of the MFN2 protein (p.Trp740Ser). The tryptophan residue is moderately conserved and there is a large physicochemical difference between tryptophan and serine. This variant is not present in population databases (rs28940292, ExAC no frequency). This variant has been reported in many individuals affected with autosomal dominant Charcot-Marie-Tooth disease (CMT), and in several cases family studies have shown that it segregates with disease (PMID: 15064763, 16714318, 21508331, 24126688). A study of a large cohort of individuals with neuropathy found that this variant accounted for 5.4% of pathogenic CMT variants detected by sequencing (PMID: 25614874). ClinVar contains an entry for this variant (Variation ID: 2269). Experimental studies have shown that while this missense change does not eliminate mitochondrial fusion (PMID: 17296794), it does cause significant impairment of mitochondrial motility in cultured dorsal root ganglion cells (PMID: 17215403, 20335458). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000235811	SCV000255676	pathogenic	not provided	2021-04-05	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant disrupts axonal mitochondrial transport (PMID: 17215403, 20335458).
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000002357	SCV000292341	pathogenic	Charcot-Marie-Tooth disease, type 2A2A	2015-08-18	criteria provided, single submitter	research	This variant has been previously reported as disease-causing and was found in a 31 yo patient with axonal neuropathy
GeneDx	RCV000235811	SCV000293110	pathogenic	not provided	2018-05-15	criteria provided, single submitter	clinical testing	The W740S missense variant in the MFN2 gene has been reported previously in association with autosomal dominant MFN2-related disorders (Verhoeven et al., 2006; Zuchner et al., 2004; Feely et al., 2011; Brozkova et al., 2013). Functional studies show that W740S alters axonal mitochondrial transport (Baloh et al., 2007; Misko et al., 2010). The W740S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The W740S 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 conserved across species. Additionally, different amino acid substitutions at the same position (W740R/C) as well as missense variants in nearby residues (S743R, E744K, L745P) have been reported in the Human Gene Mutation Database in association with CMT2 (Stenson et al., 2014), supporting the functional importance of this region of the protein.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000002357	SCV000584101	pathogenic	Charcot-Marie-Tooth disease, type 2A2A	2017-04-13	criteria provided, single submitter	research
Fulgent Genetics,Fulgent Genetics	RCV000763240	SCV000893875	pathogenic	Charcot-Marie-Tooth disease, type 2A2A; Hereditary motor and sensory neuropathy with optic atrophy; Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2A2B	2018-10-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001001747	SCV001159355	pathogenic	not specified	2018-08-17	criteria provided, single submitter	clinical testing	The MFN2 c.2219G>C; p.Trp740Ser variant (rs28940292), is reported in the literature in multiple individuals affected with Charcot-Marie-Tooth disease type 2 (Brozkova 2013, DiVincenzo 2014, Feely 2011, Gonzaga-Jauregui 2015, Verhoeven 2006, Zuchner 2004). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 2269), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Functional analyses of the variant protein in heterologous cell types shows no impact on mitochondrial fusion or oxidative activity (Baloh 2007, Detmer 2007). However, microtubule-assisted mitochondrial transport is severely impaired in neurons expressing the variant protein (Baloh 2007, Misko 2010). The tryptophan at codon 740 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, the variant is predicted to extend the coiled-coil domain at the C-terminal (Zuchner 2004). Based on available information, the p.Trp740Ser variant is considered to be pathogenic. References: Baloh R et al. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci. 2007; 27(2):422-30. Brozkova D et al. Spectrum and frequencies of mutations in the MFN2 gene and its phenotypical expression in Czech hereditary motor and sensory neuropathy type II patients. Mol Med Rep. 2013; 8(6):1779-84. Detmer S et al. Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J Cell Biol. 2007; 176(4):405-14. DiVincenzo C et al. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2014 Nov;2(6):522-9. Feely S et al. MFN2 mutations cause severe phenotypes in most patients with CMT2A. Neurology. 2011; 76(20):1690-6. Gonzaga-Jauregui C et al. Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy. Cell Rep. 2015; 12(7):1169-83. Misko A et al. Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J Neurosci. 2010; 30(12):4232-40. Verhoeven K et al. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain. 2006; 129(Pt 8):2093-102. Zuchner S et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet. 2004; 36(5):449-51.
Mayo Clinic Laboratories, Mayo Clinic	RCV000235811	SCV001715257	pathogenic	not provided	2020-07-22	criteria provided, single submitter	clinical testing	PS3, PS4, PM2, PP1, PP5
OMIM	RCV000002357	SCV000022515	pathogenic	Charcot-Marie-Tooth disease, type 2A2A	2004-05-01	no assertion criteria provided	literature only
Genesis Genome Database	RCV000857112	SCV000999687	uncertain significance	Charcot-Marie-Tooth disease	2019-08-14	no assertion criteria provided	research