ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.749G>A (p.Arg250Gln) (rs140234726)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767172 SCV000251728 uncertain significance not provided 2018-10-08 criteria provided, single submitter clinical testing The R250Q variant in the MFN2 gene has previously been reported in unrelated individuals with Charcot-Marie-Tooth neuropathy type 2A (CMT2A) who were heterozygous for R250Q, although familial segregation was not evaluated for either individual (Verhoeven et al. 2006; McCorquodale et al. 2011; Rudnik-Schöneborn et al. 2015). This variant was also identified in a patient with hereditary spastic paraplegia; however this variant did not segregate with disease in this family (Gregianin et al., 2013). In addition, R250Q was reported in two brothers with early onset sensory motor neuropathy who were compound heterozygous for the R250Q variant and another variant; the father who was heterozygous for the R250Q variant showed no symptoms of neuropathy (Tomaselli et al., 2016). The R250Q variant is observed in 50/126,720 (0.04%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The R250Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs in the critical dynamin-type G domain at a position that is conserved in mammals. Missense variants at the same residue (R250W) and in nearby residues (L248V, S249F, P251A/R/L, N252K) have been reported in the Human Gene Mutation Database in association with CMT2A (Stenson et al., 2014), further supporting the functional importance of this region of the protein. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret R250Q as a variant of uncertain significance.
Invitae RCV000464315 SCV000547925 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-11-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 250 of the MFN2 protein (p.Arg250Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs140234726, ExAC 0.04%). This variant has been reported in individuals affected with Charcot-Marie-Tooth disease type 2A (CMT2A) (PMID: 16714318, 22492563, 21258814) and in an individual affected with Charcot-Marie-Tooth disease type 1 (CMT1) (PMID:26392352). This variant has also been observed in a family with CMT (PMID: 26752306). However, in this family a pathogenic variant was also identified in LRSAM1 gene, which suggests that this c.749G>A variant was not the primary cause of disease. In addition, this variant has been reported in a family with early-onset sensory and motor neuropathy, however a second variant in MFN2 was also identified that more clearly segregated with the neuropathy phenotype, suggesting that this variant was not the primary cause of disease (PMID 26930221). ClinVar contains an entry for this variant (Variation ID: 214653). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg250 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16714318, 26306937, 28660751). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Athena Diagnostics Inc RCV000767172 SCV000614093 likely benign not provided 2019-01-30 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV000789405 SCV001337425 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789405 SCV000928760 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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