Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000814481 | SCV000954893 | likely pathogenic | Eichsfeld type congenital muscular dystrophy | 2023-08-14 | 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 268 of the SELENON protein (p.Arg268Cys). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SELENON protein function. ClinVar contains an entry for this variant (Variation ID: 657794). This missense change has been observed in individuals with congenital myopathy (PMID: 21670436, 23394784, 27066551). This variant is present in population databases (rs368074297, gnomAD 0.002%). |
Ce |
RCV001093411 | SCV001250376 | pathogenic | not provided | 2019-05-01 | criteria provided, single submitter | clinical testing | |
Broad Institute Rare Disease Group, |
RCV000814481 | SCV003761464 | likely pathogenic | Eichsfeld type congenital muscular dystrophy | 2023-01-24 | criteria provided, single submitter | curation | The p.Arg268Cys variant in SELENON has been reported in 7 individuals with SELENON-RM (PMID: 23394784, 27066551, 30932294, 32980267, 34867752) and has been identified in 0.002% (2/113102) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs368074297). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 657794) and has been interpreted as pathogenic or likely pathogenic by Invitae, CeGaT Praxis fuer Humangenetik Tuebingen, and the Pediatrics Department (Azienda Ospedaliero-Universitaria Policlinico San Marco). Of the 7 affected individuals, 3 were compound heterozygotes that carried reported pathogenic variants with unknown phase, and 2 were compound heterozygotes that carried variants of uncertain significance in trans, which increases the likelihood that the p.Arg268Cys variant is pathogenic (VariationID: 4496, 4494, 1025827, 461629, 4492; PMID: 32980267, 27066551, 30932294, 34867752, 23394784). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive SELENON-RM. ACMG/AMP Criteria applied: PP3, PM3_strong, PM2_supporting, (Richards 2015). |
Revvity Omics, |
RCV000814481 | SCV003812739 | likely pathogenic | Eichsfeld type congenital muscular dystrophy | 2023-05-16 | criteria provided, single submitter | clinical testing | |
Pediatrics Department, |
RCV000814481 | SCV001816209 | likely pathogenic | Eichsfeld type congenital muscular dystrophy | no assertion criteria provided | case-control |