ClinVar Miner

Submissions for variant NM_001005360.2(DNM2):c.1463C>G (p.Thr488Arg)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000703690 SCV000832603 likely pathogenic Charcot-Marie-Tooth disease, dominant intermediate B 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 488 of the DNM2 protein (p.Thr488Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with demyelinating neuropathy (Invitae). 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 disruptive, but 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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