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

gnomAD frequency: 0.00026  dbSNP: rs139632595

Total submissions: 13

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 Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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
GeneDx	RCV001549697	SCV001769896	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	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: 34645488, 29758258, 30690203, 31130284, 33040083, 32504085, 33258288, 34782754, 35893425, 29878067, 29727687, 30125339)
Invitae	RCV001549697	SCV002233153	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 14 of the EXOSC9 protein (p.Leu14Pro). This variant is present in population databases (rs139632595, gnomAD 0.08%). This missense change has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 29727687, 30690203). 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: 549845). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EXOSC9 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000664415	SCV002318486	pathogenic	Pontocerebellar hypoplasia, type 1D	2022-03-22	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000549845, PMID:29727687). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 29727687, 30125339). It has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 29727687) In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.606>=0.6). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000832). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000664415	SCV002764688	pathogenic	Pontocerebellar hypoplasia, type 1D	2020-11-13	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001549697	SCV002818259	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000664415	SCV003830784	likely pathogenic	Pontocerebellar hypoplasia, type 1D	2021-12-29	criteria provided, single submitter	clinical testing
OMIM	RCV000664415	SCV000788346	pathogenic	Pontocerebellar hypoplasia, type 1D	2022-05-25	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
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000664415	SCV001432950	pathogenic	Pontocerebellar hypoplasia, type 1D	2020-03-19	flagged submission	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.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000664415	SCV001469252	pathogenic	Pontocerebellar hypoplasia, type 1D	2020-10-11	no assertion criteria provided	clinical testing