ClinVar Genomic variation as it relates to human health

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).

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%).

Variant summary: SELENON c.802C>T (p.Arg268Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249328 control chromosomes (gnomAD). c.802C>T has been reported in the literature in multiple individuals affected with multi minicore disease, and congenital myopathies (examples: Scoto_2011, Maggi_2013, Tian_2015, and Bachmann_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30932294, 23394784, 21670436, 27066551). ClinVar contains an entry for this variant (Variation ID: 657794). Based on the evidence outlined above, the variant was classified as pathogenic.