Submissions for variant NM_014874.3(MFN2):c.2119C>T (p.Arg707Trp) (rs119103267)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199654	SCV000251722	likely pathogenic	not provided	2017-08-15	criteria provided, single submitter	clinical testing	The R707W variant was first reported as homozygous in an individual with severe early-onset axonal neuropathy and lipodystrophy (Nicholson et al., 2008). The parents of this individual were heterozygous carriers of R707W and had minimal clinical findings and minor electrophysiologic evidence of neuropathy. Sawyer et al., (2015) reported R707W as homozygous in brothers presenting with multiple symmetric lipomatosis (MSL) and in another unrelated individual with MSL, previously diagnosed with Charcot-Marie-Tooth disease. Compound heterozygosity involving the R707W variant and another MFN2 variant was also reported in 3 siblings, each presenting with early onset axonal neuropathy. Their heterozygous parents had no signs of peripheral neuropathy and normal electroneuromyographic findings (Calvo et al., 2009). However, there have also been reports of patients harboring the single R707W variant presenting with clinical features of CMT2 (Braathen et al., 2010) and early severe axonal CMT, including a case with a reportedly unaffected heterozygous parent (Brozkova et al., 2013). As MFN2-related disorders are incompletely penetrant, these data could be suggestive of either autosomal recessive inheritance or semi-dominant inheritance. TheR707W variant is observed in 37/66736 (0.06%) alleles from individuals of European background (Lek et al., 2016;1000 Genomes Consortium et al., 2015; Exome Variant Server). The R707W 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 conserved position predicted to be within the coiled-coil domain. A different missense variant at the same position (R707P) as well as missense variants in nearby residues (T706P, L710P) have been reported in the Human Gene Mutation Database in association with CMT2A (Stenson et al., 2014), supporting the functional importance of this region of the protein. Functional studies in fibroblasts show that R707W impairs MFN2-MFN2 protein interactions in mitochondria, making mitochondria prone to perinuclear aggregation (Sawyer et al., 2015). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000472857	SCV000547929	pathogenic	Charcot-Marie-Tooth disease, type 2	2019-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 707 of the MFN2 protein (p.Arg707Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs119103267, ExAC 0.06%). This variant has been reported in multiple individuals and families affected with Charcot Marie Tooth disease type 2 in the heterozygous, homozygous, or compound heterozygous state (PMID: 18458227, 24126688, 25025039, 22492563, 20008656), including an individual with a pathogenic variant in trans (PMID: 26114802). It has also been reported to segregate with disease (PMID: 20350294, 20008656). In addition, this variant has been reported in individuals affected with multiple symmetric lipomatosis and neuropathy (PMID: 26085578, 28414270). ClinVar contains an entry for this variant (Variation ID: 2280). Experimental studies in transfected fibroblasts have shown that this variant leads to defects in mitochondrial fusion (PMID: 26085578). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000199654	SCV000705467	pathogenic	not provided	2017-01-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624830	SCV000741959	likely pathogenic	Inborn genetic diseases	2016-09-29	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
SIB Swiss Institute of Bioinformatics	RCV000002369	SCV000803475	likely pathogenic	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2A2B	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Charcot-Marie-Tooth disease, axonal, type 2A2B, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:26085578).
Fulgent Genetics,Fulgent Genetics	RCV000763239	SCV000893874	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
Illumina Clinical Services Laboratory,Illumina	RCV000778183	SCV000914347	pathogenic	MFN2-Related Disorders	2018-12-19	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the MFN2 c.2119C>T (p.Arg707Trp) missense variant has been identified in a total of 11 individuals with MFN2-related disorders, including in a homozygous state in four individuals, (two of whom are related), in a compound heterozygous state in four individuals, and in a heterozygous state in three individuals (Nicholson et al. 2008; Calvo et al. 2009; Braathen et al. 2010; Sitarz et al. 2012; Brozkova et al. 2013; Hoyer et al. 2014; Sawyer et al. 2015; Carr et al. 2015). The variant was also found in a heterozygous state in several asymptomatic parents, consistent with an autosomal recessive pattern of inheritance. MFN2-related disorders have also been reported to follow an autosomal dominant pattern of inheritance which was observed through four generations of one family in a study by Braathen et al. (2010). The p.Arg707Trp variant was absent from at least 602 evaluated control alleles (Nicholson et al. 2008; Braathen et al. 2010) and is reported at a frequency of 0.000581 in the European American population of the Exome Sequencing Project. Functional studies in U2OS cells homozygous for the p.Arg707Trp variant demonstrate a reduced ability to form homotypic MFN2 protein interactions in vitro and to tubulate mitochondria which were more prone to aggregation (Sawyer et al. 2015). The p.Arg707Trp variant is located in a well-conserved residue in a known functional domain that is thought to permit homotypic protein interaction as well as heterotypic binding to MFN1 (Sawyer et al. 2015). Based on the collective evidence, the p.Arg707Trp variant is classified as pathogenic for MFN2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000239892	SCV000966809	likely pathogenic	Charcot-Marie-Tooth disease, type 2A2A	2019-02-11	criteria provided, single submitter	clinical testing	The p.Arg707Trp variant in MFN2 has been reported in the heterozygous state in 4 probands with clinical features of Charcot-Marie-Tooth disease type 2A (CMT2A; Braathen 2010, Sitarz 2012, Brozkova 2013, Bansagi 2017). It has also been repor ted in the compound heterozygous or homozygous state in at least 9 individuals w ith CMT2A-related neuropathy and lipomatosis or lipodystrophy (Nicholson 2008, C alvo 2009, Carr 2015, Sawyer 2015, Rocha 2017, Capel 2018). The variant segregat ed with neuropathy and lipomatosis/lipodystrophy in at least 4 affected members of 3 families (Calvo 2009, Rocha 2017, Capel 2018). This variant has also been i dentified in the heterozygous state in individuals without overt signs of neurop athy (Nicholson 2008, Calvo 2009, Brozkova 2013, Carr 2015, Rocha 2017) and in 0 .05% (66/129186) of European chromosomes by gnomAD (http://gnomad.broadinstitute .org). However, this is consistent with the fact that variable expressivity incl uding sub-clinical, late-onset neuropathy has been reported for CMT2A (Zuchner 2 013). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. Furthermore, analysis of patient fibroblasts sugge st that the p.Arg707Trp variant may impair mitochondrial function (Sawyer 2015). In summary, although additional studies are required to fully establish its cli nical significance, the p.Arg707Trp variant meets criteria to be classified as l ikely pathogenic for autosomal dominant CMT2A, with homozygous or compound heter oygous occurences likely leading to a more severe course of disease that may inc lude lipomatosis and/or lipodystrophy. ACMG/AMP Criteria applied: PM3_Strong, PP 3, PS3_Supporting, PS4_Supporting.
OMIM	RCV000002369	SCV000022527	pathogenic	Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2A2B	2008-05-06	no assertion criteria provided	literature only
OMIM	RCV000239892	SCV000298222	pathogenic	Charcot-Marie-Tooth disease, type 2A2A	2008-05-06	no assertion criteria provided	literature only