ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.436C>T (p.Leu146Phe) (rs863224969)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201006 SCV000255682 likely pathogenic Charcot-Marie-Tooth disease, type 2A2A 2015-08-07 criteria provided, single submitter clinical testing
GeneDx RCV000237022 SCV000293527 likely pathogenic not provided 2017-01-31 criteria provided, single submitter clinical testing The L146F variant has been previously reported to segregate with the phenotype in a large family with CMT2A2 (Klein et al., 2011). The age of onset and severity of the disease varied greatly among the affected relatives (Klein et al., 2011). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the L146F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

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