ClinVar

Description

The heterozygous p.Ala45ValfsTer2 variant in BET1 was identified by our study in trans with a VUS missense variant in one individual with progressive muscular weakness and seizures. This variant has been identified in 0.018% (24/128800) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs541754296). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 45 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. While this alteration is then predicted to lead to a truncated or absent protein, this variant was detectable in the muscle RNA. However, western blot analysis showed reduced to absent BET1 in patient fibroblasts compared to controls. Of note, loss of function of the BET1 gene in autosomal dominant disease has not yet been established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain.