Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000458536 | SCV000548857 | likely pathogenic | Charcot-Marie-Tooth disease type 2 | 2017-06-19 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine with serine at codon 373 of the LMNA protein (p.Ile373Ser). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with LMNA-related disease (Invitae). Different missense substitutions at this codon (p.Ile373Val, p.Ile373Asn) have been reported in individuals affected with LMNA-associated congenital muscular dystrophy (L-CMD) (PMID:26098624). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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. |