ClinVar Miner

Submissions for variant NM_014874.3(MFN2):c.839G>A (p.Arg280His) (rs28940294)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000236600 SCV000255685 pathogenic not provided 2017-09-14 criteria provided, single submitter clinical testing
GeneDx RCV000236600 SCV000293529 pathogenic not provided 2018-09-20 criteria provided, single submitter clinical testing The R280H missense variant in the MFN2 gene has been reported previously in association with both early onset and late onset Charcot-Marie-Tooth disease type 2A (Zuchner et al., 2004; Verhoeven et al., 2006; Liesa et al., 2009), and the R280 position is considered a mutational hotspot (Verhoeven et al., 2006; Liesa et al., 2009). Functional studies of the R280H variant demonstrate a damaging effect with lack of mitochondrial fusion activity (Detmer et al., 2007). The R208H variant is not observed in large population cohorts (Lek et al., 2016). We interpret R280H as a pathogenic variant.
Invitae RCV000549934 SCV000657731 pathogenic Charcot-Marie-Tooth disease, type 2 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 280 of the MFN2 protein (p.Arg280His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs28940294, ExAC 0.002%). This variant has been reported in individuals affected with Charcot-Marie-Tooth disease, type 2A (PMID: 15064763, 27549087, 16714318, 24957169, 22492563, 21149811, 27027447, 27088055) and has been reported to segregate with disease in multiple families (PMID: 15064763, 16835246). ClinVar contains an entry for this variant (Variation ID: 2271) Experimental studies have shown that this variant affects the proper transport of mitochondria by the MFN2 protein in neurons (PMID: 17296794, 17215403). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000002359 SCV001149834 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2019-04-05 criteria provided, single submitter clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center RCV000002359 SCV001167080 pathogenic Charcot-Marie-Tooth disease, type 2A2A criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV000789418 SCV001336792 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000236600 SCV001447019 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
OMIM RCV000002359 SCV000022517 pathogenic Charcot-Marie-Tooth disease, type 2A2A 2006-08-01 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000789418 SCV000928773 pathogenic Charcot-Marie-Tooth disease no assertion criteria provided literature only

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.