ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
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.
Invitae RCV001386993 SCV001587457 pathogenic Charcot-Marie-Tooth disease, type 2 2020-07-08 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 146 of the MFN2 protein (p.Leu146Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant MFN2-related neuropathy (PMID: 21987543, 27549087). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217163). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.