VCV000549845.28 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 549845 Accession: VCV000549845.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q27 4: 121801465 (GRCh38) [ NCBI UCSC ] 4: 122722620 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 4, 2018	Sep 29, 2024	May 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005033.3:c.41T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005024.2:p.Leu14Pro	missense
NM_001034194.2(EXOSC9):c.41T>C		missense
NM_001034194.2:c.41T>C	NP_001029366.1:p.Leu14Pro	missense
NC_000004.12:g.121801465T>C
NC_000004.11:g.122722620T>C
NG_029848.1:g.5149T>C

... more HGVS ... less HGVS

Protein change

L14P

Other names

EXOSC9, LEU14PRO (rs139632595)

Canonical SPDI

NC_000004.12:121801464:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00024

The Genome Aggregation Database (gnomAD) 0.00026

Links

OMIM: 606180.0001 dbSNP: rs139632595 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
EXOSC9		-	-	GRCh38 GRCh37	266	309

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Pontocerebellar hypoplasia, type 1D	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Mar 14, 2024	RCV000664415.27
Cerebral atrophy	Likely pathogenic (1)	criteria provided, single submitter	Oct 1, 2020	RCV001260241.4
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 17, 2024	RCV001549697.14

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Pontocerebellar hypoplasia, type 1D Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136766.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely pathogenic (Oct 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Cerebral atrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001437160.1 First in ClinVar: Oct 07, 2020 Last updated: Oct 07, 2020	Comment: 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 … (more) 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). (less)
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia, type 1D Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV005038894.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia, type 1D Affected status: yes Allele origin: biparental	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001554500.2 First in ClinVar: Apr 13, 2021 Last updated: Mar 01, 2022	Publications: PubMed (1) PubMed: 34782754
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia, type 1D Affected status: yes Allele origin: germline	3billion Accession: SCV002318486.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (2) PubMed: 29727687‚ 30125339 Comment: 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 … (more) 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. (less) Clinical Features: Global developmental delay (present) , Generalized hypotonia (present)
Pathogenic (Nov 13, 2020)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Pontocerebellar hypoplasia, type 1D (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV002764688.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Hip dislocation (present) , Decreased activity of mitochondrial complex I (present) , Left ventricular systolic dysfunction (present) , Abnormality of mitochondrial metabolism (present) , Scoliosis … (more) Hip dislocation (present) , Decreased activity of mitochondrial complex I (present) , Left ventricular systolic dysfunction (present) , Abnormality of mitochondrial metabolism (present) , Scoliosis (present) , Decreased activity of mitochondrial complex IV (present) , Tetraparesis (present) , Seizure (present) , Decreased activity of mitochondrial complex II (present) (less)
Pathogenic (Dec 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV002818259.1 First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023
Pathogenic (Jan 22, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002233153.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 29727687‚ 30690203 Comment: 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). … (more) 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. (less)
Pathogenic (May 17, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001769896.5 First in ClinVar: Aug 07, 2021 Last updated: Sep 29, 2024	Comment: 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, … (more) 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) (less)
Likely pathogenic (Dec 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia, type 1D Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003830784.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jun 15, 2018)	no assertion criteria provided Method: clinical testing	Pontocerebellar hypoplasia, type 1D (Autosomal recessive inheritance) Affected status: yes, no Allele origin: inherited	Centre for Arab Genomic Studies, Sheikh Hamdan Award for Medical Sciences Accession: SCV000863570.2 First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018	Observation 1: Clinical Features: Failure to thrive (present) , Short stature (present) , Microbrachycephaly (present) , Hypotonia (present) , Cerebellar atrophy (present) , Cerebellar vermis atrophy (present) , Global … (more) Failure to thrive (present) , Short stature (present) , Microbrachycephaly (present) , Hypotonia (present) , Cerebellar atrophy (present) , Cerebellar vermis atrophy (present) , Global developmental delay (present) , Dysphagia (present) , Hyperextensible hand joints (present) , Sacral dimple (present) (less) Family history: yes Age: 0-9 years Sex: female Ethnicity/Population group: Emirati Geographic origin: United Arab Emirates Segregation observed: yes Observation 2: Clinical Features: Reduced brain N-acetyl aspartate level by MRS (present) , Elevated brain choline level by MRS (present) , Elevated brain lactate level by MRS (present) , … (more) Reduced brain N-acetyl aspartate level by MRS (present) , Elevated brain choline level by MRS (present) , Elevated brain lactate level by MRS (present) , Cerebral atrophy (present) , Cerebellar atrophy (present) , Cerebellar vermis atrophy (present) , Lactic acidosis (present) , Diffuse white matter abnormalities (present) , Global developmental delay (present) , Feeding difficulties (present) , Multiple palmar creases (present) (less) Family history: yes Age: 0-9 years Sex: female Ethnicity/Population group: Emirati Geographic origin: United Arab Emirates Segregation observed: yes Observation 3: Family history: yes Sex: male Ethnicity/Population group: Emirati Geographic origin: United Arab Emirates Segregation observed: yes Observation 4: Family history: yes Sex: female Ethnicity/Population group: Emirati Geographic origin: United Arab Emirates Segregation observed: yes Observation 5: Family history: yes Sex: male Ethnicity/Population group: Emirati Geographic origin: United Arab Emirates Segregation observed: yes Observation 6: Family history: yes Sex: female Ethnicity/Population group: Emirati Geographic origin: United Arab Emirates Segregation observed: yes Observation 7: Family history: yes Sex: female Ethnicity/Population group: Emirati Geographic origin: United Arab Emirates Segregation observed: yes Observation 8: Family history: yes Sex: female Ethnicity/Population group: Emirati Geographic origin: United Arab Emirates Segregation observed: yes Observation 9: Family history: yes Sex: female Ethnicity/Population group: Emirati Geographic origin: United Arab Emirates Segregation observed: yes
Pathogenic (Oct 11, 2020)	no assertion criteria provided Method: clinical testing	Pontocerebellar hypoplasia, type 1D Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001469252.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Pathogenic (May 25, 2022)	no assertion criteria provided Method: literature only	PONTOCEREBELLAR HYPOPLASIA, TYPE 1D Affected status: not provided Allele origin: germline	OMIM Accession: SCV000788346.4 First in ClinVar: Jul 30, 2018 Last updated: May 28, 2022	Publications: PubMed (1) PubMed: 29727687 Bizzari, S., Hamzeh, A. R., (more...) Bizzari, S., Hamzeh, A. R., Mohamed, M., Al-Ali, M. T., Bastaki, F. Expanded PCH1D phenotype linked to EXOSC9 mutation. Europ. J. Med. Genet. 63: 103622, 2020. Note: Electronic Article. Comment on evidence: In 3 unrelated patients (individuals 1, 3, and 4) with pontocerebellar hypoplasia type 1D (PCH1D; 618065), Burns et al. (2018) identified a homozygous c.41T-C transition … (more) In 3 unrelated patients (individuals 1, 3, and 4) with pontocerebellar hypoplasia type 1D (PCH1D; 618065), Burns et al. (2018) identified a homozygous c.41T-C transition (NG_029848.1) in the EXOSC9 gene, resulting in a leu14-to-pro (L14P) substitution. The mutation in individual 1, who was a 28-month-old girl born of unrelated parents from El Salvador, was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing. Individual 3 was a 4.5-year-old girl born of consanguineous Saudi Arabian parents, and individual 4 was a 19-month-old girl born of unrelated parents of African, European, and Filipino ancestry. The mutation segregated with the disorder in all 3 families, and haplotype analysis suggested a common ancestor. The L14P variant was found 6 times in heterozygous state in the ExAC database in individuals of African descent (allele frequency of 4.947 x 10(-5)), but not in individuals of Hispanic descent. Another patient (individual 2), an unrelated boy of African, Canadian, and Jamaican descent who died at age 15 months, was compound heterozygous for L14P and a c.481C-T transition in the EXOSC9 gene, resulting in an arg161-to-ter (R161X; 606180.0002) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in this family. The R161X mutation was listed 3 times in heterozygous state in the ExAC database. Immunoblotting of cells from individuals 1 and 2 showed decreased levels of the EXOCS9 protein, suggesting instability or reduced assembly and function of the exosome complex. In 2 unrelated Emirati girls with PCH1D, who were both born to consanguineous parents, Bizzari et al. (2020) identified homozygosity for a c.41T-C transition (c.41T-C, NM_001034194.1) in the EXOSC9 gene, resulting in a leu14-to-pro substitution. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in both sets of parents. The mutation was predicted to result in protein instability. The variant was present at an allele frequency of 0.00007 in the African population in the gnomAD database. (less)
Pathogenic (Mar 19, 2020)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV001432950 appears to (...more) Source: NCBI	Pontocerebellar Hypoplasia, Type 1d Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV001432950.1 First in ClinVar: Sep 23, 2020 Last updated: Sep 23, 2020	Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1 Sex: male
click to load more click to collapse
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

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).

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Accelerated genome sequencing with controlled costs for infants in intensive care units: a feasibility study in a French hospital network.	Denommé-Pichon AS	European journal of human genetics : EJHG	2022	PMID: 34782754
Expanded PCH1D phenotype linked to EXOSC9 mutation.	Bizzari S	European journal of medical genetics	2020	PMID: 30690203
Reanalysis of exome sequencing data of intellectual disability samples: Yields and benefits.	Al-Nabhani M	Clinical genetics	2018	PMID: 30125339
Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.	Burns DT	American journal of human genetics	2018	PMID: 29727687

Text-mined citations for rs139632595 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs139632595 ...