Submissions for variant NM_014874.4(MFN2):c.838C>T (p.Arg280Cys)

dbSNP: rs879253957

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235764	SCV000292947	likely pathogenic	not provided	2023-08-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24863639, 32123317, 25614874, 33879512)
Revvity Omics, Revvity	RCV000235764	SCV002022789	likely pathogenic	not provided	2023-07-20	criteria provided, single submitter	clinical testing
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV002307469	SCV002600205	likely pathogenic	Multiple system atrophy, cerebellar type	2022-05-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005055788	SCV005701070	likely pathogenic	Charcot-Marie-Tooth disease type 2	2024-06-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 280 of the MFN2 protein (p.Arg280Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 33879512). ClinVar contains an entry for this variant (Variation ID: 245809). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MFN2 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg280 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15064763, 16835246, 24957169, 27088055, 27549087). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.