ClinVar Miner

Submissions for variant NM_005033.3(EXOSC9):c.41T>C (p.Leu14Pro) (rs139632595)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000664415 SCV001136766 pathogenic Pontocerebellar hypoplasia, type 1d 2019-05-28 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000664415 SCV001430747 uncertain significance Pontocerebellar hypoplasia, type 1d 2020-05-27 criteria provided, single submitter research 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 and Sheikh Hamdan Award for Medical Sciences in ClinVar (Variation ID: 549845). In vitro functional studies provide some evidence that the p.Leu14Pro variant may slightly 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. The presence of this variant in 5 affected homozygotes increases the likelihood that the p.Leu14Pro variant is pathogenic (PMID: 29727687). In summary, the clinical significance of the p.Leu14Pro variant is uncertain.
Al Jalila Children's Genomics Center,Al Jalila Childrens Speciality Hospital RCV000664415 SCV001432950 pathogenic Pontocerebellar hypoplasia, type 1d 2020-03-19 criteria provided, single submitter clinical testing The p.Leu14Pro variant in EXOSC9 has been previously reported in the homozygous state in 5 unrelated individuals affected with Cerebellar Atrophy With Spinal Motor Neuronopathy (PMID: 29727687, 30125339, 29878067) and in another affected individual who was compound heterozygous with another pathogenic loss of function variant in EXOSC9 (PMID: 29727687). Functional analysis of patient fibroblasts and skeletal muscle showed reduced EXOSC9 protein expression along with reduction of the whole multi-subunit exosome complex (PMID: 29727687). Furthermore, RNA sequencing of patient cells detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration. Studies in zebrafish recapitulate aspects of the human phenotype (PMID: 29727687). The p.Leu14Pro variant is observed in 21/24970(0.084%; 0 homozygotes) African alleles in the Genome Aggregation Database (gnomAD). In summary this variant meets our criteria to be classified as pathogenic. This variant is found in homozygous state in the individual and heterozygous state in both the parents, who are reported to be consanguineous. The clinical features of the patient highly correlate with the reported features of other patients carrying this variant. Recessive variants in EXOSC9 are associated with Pontocerebellar hypoplasia, type 1d, a severe, early onset progressive, SMS-like motor neuronopathy and cerebellar atrophy.
Broad Institute Rare Disease Group, Broad Institute RCV001260241 SCV001437160 likely pathogenic Cerebral atrophy 2020-10-01 criteria provided, single submitter research 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).
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000664415 SCV001554500 pathogenic Pontocerebellar hypoplasia, type 1d criteria provided, single submitter clinical testing
OMIM RCV000664415 SCV000788346 pathogenic Pontocerebellar hypoplasia, type 1d 2020-12-17 no assertion criteria provided literature only
Centre for Arab Genomic Studies,Sheikh Hamdan Award for Medical Sciences RCV000664415 SCV000863570 pathogenic Pontocerebellar hypoplasia, type 1d 2018-06-15 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000664415 SCV001469252 pathogenic Pontocerebellar hypoplasia, type 1d 2020-10-11 no assertion criteria provided clinical testing

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