ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.1537A>G (p.Ile513Val) (rs755657087)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506384 SCV000604225 uncertain significance not specified 2017-04-28 criteria provided, single submitter clinical testing
GeneDx RCV000657919 SCV000779686 uncertain significance not provided 2018-03-09 criteria provided, single submitter clinical testing The c.1537A>G variant in the MFN2 gene has been reported previously, along with another variant, in an individual with CMT2A (Bombelli et al., 2014). The c.1537A>G variant is observed in 4/126714 (0.0032%) alleles from individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). In silico splice models predict that c.1537A>G may create a cryptic splice donor site upstream that could supplant the natural splice donor site of intron 15. However, in the absence of RNA/functional studies, the actual effect of the c.1537A>G change in this individual is unknown. If c.1537A>G does not alter splicing, it will result in the I513V missense change. The I513V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret c.1537A>G as a variant of uncertain significance.
Invitae RCV000810445 SCV000950644 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-07-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 513 of the MFN2 protein (p.Ile513Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs755657087, ExAC 0.003%). This variant has been observed in combination with another MFN2 variant in an individual affected with Charcot-Marie-Tooth disease (PMID: 24957169). ClinVar contains an entry for this variant (Variation ID: 439899). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000789379 SCV000928734 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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