ClinVar

Description

The homozygous p.Leu14Pro variant in EXOSC9 was identified by our study in an individual with pontocerebellar hypoplasia (PMID: 29727687). The p.Leu14Pro variant has also been reported in 5 additional individuals with pontocerebellar hypoplasia (PMID: 29727687, 30690203, 30125339), and has been identified in 0.084% (21/24970) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139632595). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has been reported pathogenic by OMIM, Al Jalila Children's Genomics Center,Al Jalila Childrens Speciality Hospital, Sheikh Hamdan Award for Medical Sciences, and Mendelics in ClinVar (Variation ID: 549845). Of the 6 affected individuals, 5 of those were homozygotes and 1 was a compound heterozygote that carried a reported likely pathogenic variants in trans, which increases the likelihood that the p.Leu14Pro variant is pathogenic (PMID: 29727687, 30690203, 30125339). The phenotype of individuals homozygous for this variant is highly specific for pontocerebellar hypoplasia based on the unique phenotype consistent with disease (PMID: 29727687). In vitro functional studies provide some evidence that the p.Leu14Pro variant may impact protein function (PMID: 29727687). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive pontocerebellar hypoplasia. ACMG/AMP Criteria applied: PM3_strong, PS3_moderate, PP4 (Richards 2015).