ClinVar

Description

The p.Ala276_Cys277insSer variant in SELENON has been reported in 2 individuals with SELENON-RM (PMID: 30932294, 26780752) and has been identified in 0.007% (2/30600) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1329981323). 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#: 212149) and has been interpreted as likely pathogenic by GeneDx and Genetic Services Laboratory (University of Chicago). Of the 2 affected individuals, both were homozygotes, which increases the likelihood that the p.Ala276_Cys277insSer variant is pathogenic (PMID: 30932294, 26780752). In vitro functional studies provide some evidence that the p.Ala276_Cys277insSer variant may impact protein function (PMID: 30932294). However, these types of assays may not accurately represent biological function. This variant is an insertion of 1 amino acid at position 276 and is not predicted to alter the protein reading-frame. This insertion is expected to impact the protein. 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: PM3, PS3_moderate, PM2_supporting, PM4_supporting (Richards 2015).