ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.1574A>G (p.Asn525Ser) (rs145654854)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199695 SCV000251702 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing The N525S variant has previously been reported in a single family with inherited peripheral neuropathy however detailed clinical or segregation information was not provided (Laaauthova et al. 2016). The N525S variant is observed in 16/30782 (0.05%) alleles from individuals of South Asian background (Lek et al., 2016). The N525S 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. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000692017 SCV000819822 uncertain significance Charcot-Marie-Tooth disease, type 2 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 525 of the MFN2 protein (p.Asn525Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant has not been published in the literature and is present in population databases (rs145654854, 0.05%). This variant has been reported in an individual affected with inherited peripheral neuropathies (IPN) (PMID: 27549087). The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In addition, 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. However, algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has also not been confirmed by published experimental studies. In summary, this is a rare missense change that is not predicted to affect protein function and has uncertain impact on splicing. Although there is no indication that this variant causes disease, the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Genetics Laboratory,London Health Sciences Centre RCV001174302 SCV001337434 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing

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