Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000057136 | SCV000279221 | pathogenic | not provided | 2018-08-08 | criteria provided, single submitter | clinical testing | The N98S pathogenic variant in the NEFL gene has been reported multiple times previously (as N97S in some publications due to alternative nomenclature) in association with CMT (Yoshihara et al., 2002; Jordanova et al., 2003; Abe et al., 2009; Baets et al., 2011; Berciano et al., 2015). The N98S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N98S variant is a conservative amino acid substitution. This substitution occurs at a position that is conserved across species. Functional analysis in a cell line derived from an individual harboring the N98S variant demonstrated reduced mitochondrial mobility in axons compared to age-matched controls, and abnormal accumulation of neurofilament proteins in the cell body likely due to abnormal trafficking of the protein (Saporta et al., 2015). |
| Invitae | RCV000554079 | SCV000639659 | pathogenic | Charcot-Marie-Tooth disease type 2E | 2018-07-09 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine with serine at codon 98 of the NEFL protein (p.Asn98Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Charcot-Marie-Tooth disease (PMID: 19158810, 21840889, 25448007, 12477167, 27206872, 26645395). This variant has also been shown to arise de novo in one individual affected with Charcot-Marie-Tooth disease (PMID: 12566280). This variant is also known as p.Asn97Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 41236). Experimental studies in knock-in mice show that this missense substitution leads to NEFL protein aggregates in neurons and a decrease in neurofilament number and axon size (PMID: 25552649). In addition, cultured motor neurons derived from stem cells from an affected individual carrying this variant show cytoskeletal abnormalities (PMID: 25448007). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000034136 | SCV000058067 | pathologic | Charcot-Marie-Tooth disease, demyelinating, type 1f | 2012-10-18 | no assertion criteria provided | curation | Converted during submission to Pathogenic. |
| Epithelial Biology; Institute of Medical Biology, |
RCV000057136 | SCV000088249 | not provided | not provided | no assertion provided | not provided | ||
| OMIM | RCV000585792 | SCV000693719 | pathogenic | CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE G | 2018-03-06 | no assertion criteria provided | literature only |