ClinVar Genomic variation as it relates to human health

Variant summary: SELENON c.872G>A (p.Arg291Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site and three also predict the variant creates a cryptic intronic 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 249064 control chromosomes (gnomAD). c.872G>A has been reported in the literature in multiple individuals affected with Eichsfeld Type Congenital Muscular Dystrophy (Makri_2007, Scoto_2011, Dragoumi_2019, Villar-Quiles_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The heterozygous p.Arg291Gln variant in SELENON was identified by our study in the compound heterozygous state, along with a pathogenic variant, in one individual with SELENON-RM, however the phase of these variants are unknown at this time. The variant has been reported in 3 individuals with SELENON-RM (PMID: 21670436, Makri 2007, Dragoumi 2019) and has been identified in 0.003% (3/112914) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs199564797). 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#: 280026) and has been interpreted as likely pathogenic or pathogenic by Invitae, GeneDx, Undiagnosed Diseases Network (NIH), CeGaT Praxis fuer Humangenetik Tuebingen, Women's Health and Genetics/Laboratory Corporation of America (LabCorp). Of the 3 additional affected individuals, 1 of those was a homozygote, and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Arg291Gln variant is pathogenic (VariationID: 4492; Makri 2007, Dragoumi 2019). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Arg291Gln have been reported in association with disease in ClinVar, suggesting that this variant is in a hot spot and slightly supports 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: PM2, PM3, PP3, PM1_supporting (Richards 2015).

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21670436, 34426522, 32796131, 35368679)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 291 of the SELENON protein (p.Arg291Gln). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (rs199564797, gnomAD 0.003%). This missense change has been observed in individual(s) with SELENON-related myopathy (PMID: 21670436; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 280026). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic.

ACMG categories: PS1,PM1,PM2,BP1