ClinVar Genomic variation as it relates to human health
NM_016042.4(EXOSC3):c.395A>C (p.Asp132Ala)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_016042.4(EXOSC3):c.395A>C (p.Asp132Ala)
Variation ID: 31688 Accession: VCV000031688.72
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9p13.2 9: 37783993 (GRCh38) [ NCBI UCSC ] 9: 37783990 (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 Feb 27, 2015 Aug 4, 2024 Jan 30, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_016042.4:c.395A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057126.2:p.Asp132Ala missense NM_001002269.2:c.395A>C NP_001002269.1:p.Asp132Ala missense NC_000009.12:g.37783993T>G NC_000009.11:g.37783990T>G NG_032780.1:g.6100A>C Q9NQT5:p.Asp132Ala - Protein change
- D132A
- Other names
- -
- Canonical SPDI
- NC_000009.12:37783992:T:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00032
Trans-Omics for Precision Medicine (TOPMed) 0.00036
The Genome Aggregation Database (gnomAD), exomes 0.00041
The Genome Aggregation Database (gnomAD) 0.00048
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00085
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 | ||
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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. |
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EXOSC3 | - | - |
GRCh38 GRCh37 |
243 | 333 |
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. |
---|---|---|---|---|
Pathogenic (24) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2024 | RCV000024366.50 | |
Pathogenic (1) |
criteria provided, single submitter
|
Aug 3, 2021 | RCV000190687.14 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2023 | RCV000224817.36 | |
Pathogenic (1) |
criteria provided, single submitter
|
Sep 4, 2016 | RCV000761614.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2021 | RCV001836713.9 | |
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Dec 21, 2022 | RCV003156064.8 |
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. |
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Pathogenic
(Dec 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746484.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
Age: 0-9 years
Sex: male
Geographic origin: Iran
|
|
Pathogenic
(Mar 08, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000706778.2
First in ClinVar: Oct 05, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
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Pathogenic
(Dec 03, 2018)
|
criteria provided, single submitter
Method: research
|
Pontocerebellar hypoplasia type 1B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164439.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The homozygous p.Asp132Ala variant in EXOSC3 was identified by our study in one individual with pontocerebellar hypoplasia. The p.Asp132Ala variant in EXOSC3 has been reported … (more)
The homozygous p.Asp132Ala variant in EXOSC3 was identified by our study in one individual with pontocerebellar hypoplasia. The p.Asp132Ala variant in EXOSC3 has been reported in 28 individuals with pontocerebellar hypoplasia, segregated with disease in 28 individuals with pontocerebellar hypoplasia with a variety of ethnic backgrounds (including Cuban, Canadian, European, Turkish, American, and Australian) and segregated with disease in 4 affected relatives from 2 families (PMID: 29656927, 22544365, 23975261, 24524299), and has been identified in 0.07279% (94/129130) of European (non-Finnish) chromosome by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141138948). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservational analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with 8 variants (including 3 loss of function variants) and in individuals with pontocerebellar hypoplasia increases the likelihood that the p.Asp132Ala variant is pathogenic (PMID: 23975261, 22544365, 24524299; Variation ID: 129024, 31690, 488793, 31689). In summary, this variant meets criteria to be classified as pathogenic for pontocerebellar hypoplasia in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with reported pathogenic EXOSC3 variants in individuals with the disease. ACMG/AMP Criteria applied: PM2, PP3, PM3_VeryStrong, PP1_Moderate (Richards 2015). (less)
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Pathogenic
(Sep 30, 2020)
|
criteria provided, single submitter
Method: research
|
Pontocerebellar hypoplasia type 1B
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Cologne University
Accession: SCV001441229.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002061270.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.395A>C;p.(Asp132Ala) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 31688; PMID: 23975261; 28687512; 30986545; … (more)
The c.395A>C;p.(Asp132Ala) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 31688; PMID: 23975261; 28687512; 30986545; 23564332; 23564332; 29656927; 24524299; 27146152; 24970098; 23883322; 22544365) -. PS4.The variant is present at low allele frequencies population databases (rs141138948– gnomAD 0.004796%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Asp132Ala) was detected in trans with a pathogenic variant (PMID: 23975261; 28687512; 23564332; 23564332; 24524299; 24524299; 27146152) -PM3_very strong The variant co-segregated with disease in multiple affected family members (PMID: 23975261; 30986545; 23564332; 27146152) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
|
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Pathogenic
(Oct 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000247328.2
First in ClinVar: Oct 05, 2015 Last updated: Jan 29, 2022 |
|
|
Pathogenic
(Sep 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512573.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 very strong, PP1 strong, PP3 supporting
Geographic origin: Brazil
|
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Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580858.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PP1_STR, PS4_MOD, PM3, PM2_SUP, PP3
|
Number of individuals with the variant: 1
Sex: male
|
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Pathogenic
(Mar 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764687.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Microcephaly (present) , Motor delay (present) , Hypokinesia (present) , Hypotonia (present)
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV003924041.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
A Homozygote Missense variant c.395A>C in Exon 2 of the EXOSC3 gene that results in the amino acid substitution p.Asp132Ala was identified. The observed variant … (more)
A Homozygote Missense variant c.395A>C in Exon 2 of the EXOSC3 gene that results in the amino acid substitution p.Asp132Ala was identified. The observed variant has a minor allele frequency of 0.00041/0.00041% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 31688 as of 2022-12-24). The c.395A>C, p.Asp132Ala missense variant identified in the EXOSC3 gene has been reported previously in multiple unrelated individuals with pontocerebellar hypoplasia type 1 (Wan, Jijun et al., 2012). Functionally, the variant causes dysfunctional exosome complex (Schottmann, Gudrun et al., 2017). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
|
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Pathogenic
(Dec 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004801434.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The EXOSC3 c.395A>C p.(Asp132Ala) missense variant has been identified in individuals with a phenotype consistent with pontocerebellar hypoplasia (Wan et al. 2012; Biancheri et al. … (more)
The EXOSC3 c.395A>C p.(Asp132Ala) missense variant has been identified in individuals with a phenotype consistent with pontocerebellar hypoplasia (Wan et al. 2012; Biancheri et al. 2013; Rudnik-Schöneborn et al. 2013; Zanni et al. 2013; Eggens et al. 2014; Schottman et al. 2017). At least one study indicated that a milder phenotype was observed when the variant was present in a homozygous state, but was more severe in individuals carrying the variant in a compound heterozygous state (Rudnik-Schöneborn et al. 2013). The highest frequency of this allele in the Genome Aggregation Database is 0.000904 in the European (non-Finnish) population (version 2.1.1). Morpholino knockdown of exosc3 in zebrafish embryos recapitulated the human phenotype; rescue of the abnormal phenotype was less effective with variant protein than wildtype protein (Wan et al. 2012). Functional studies in patient fibroblasts showed that the variant protein was largely retained in the cytosol and Golgi system compared with the speckled distribution in the nucleus of control cells (Schottman et al. 2017). Additionally, structural models in yeast Rrp40 demonstrate that the p.Asp132Ala variant impairs formation of a loop in the S1 domain, which is essential for interfacing with EXOSC5 and EXOSC9 (Fasken et al. 2017). Based on the collective evidence, the c.395A>C p.(Asp132Ala)variant is classified as pathogenic for pontocerebellar hypoplasia. (less)
|
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Pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001962180.18
First in ClinVar: Oct 08, 2021 Last updated: Aug 04, 2024 |
Comment:
EXOSC3: PM3:Very Strong, PP1:Strong, PM2
Number of individuals with the variant: 7
|
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Pathogenic
(Jun 18, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281509.2
First in ClinVar: Jun 08, 2016 Last updated: Oct 09, 2016 |
|
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Pathogenic
(Mar 07, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia, type 1B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
|
Clinical Genetics, University of Leipzig
Accession: SCV000886743.1
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
Pathogenic
(Sep 04, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypotonia
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV000891781.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
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Pathogenic
(Jan 04, 2021)
|
criteria provided, single submitter
Method: research
|
Pontocerebellar hypoplasia type 1B
Affected status: yes
Allele origin:
inherited
|
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris
Accession: SCV001519132.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
|
Pathogenic
(Jun 30, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
Affected status: unknown
Allele origin:
inherited
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001761026.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
Comment:
The c.395A>C, p.Asp132Ala missense variant identified in the EXOSC3 gene has been reported previously in multiple unrelated individuals with pontocerebellar hypoplasia type 1 [PMID: 22544365; … (more)
The c.395A>C, p.Asp132Ala missense variant identified in the EXOSC3 gene has been reported previously in multiple unrelated individuals with pontocerebellar hypoplasia type 1 [PMID: 22544365; PMID: 25149867; PMID: 23975261; PMID: 24524299; PMID: 29656927]. This variant has a frequency of 0.05% (69 heterozygous out of 143304 alleles) in gnomAD database which is low enough to be consistent with a recessive carrier frequency. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the available evidence, the variant c.395A>C, p.Asp132Ala in the EXOSC3 gene is classified as pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Esotropia (present) , Hypotonia (present)
Secondary finding: no
|
|
Pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormality of the nervous system
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV000891780.2
First in ClinVar: Mar 31, 2019 Last updated: Feb 20, 2022 |
|
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Pathogenic
(Oct 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061676.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 13, 2022 |
Comment:
PM3_VS, PP1, PP3, PM2
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
Affected status: yes
Allele origin:
inherited
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559164.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
|
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Pathogenic
(Sep 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000807246.2
First in ClinVar: May 03, 2018 Last updated: Dec 11, 2022 |
Comment:
This mutation has been previously reported as disease-causing and was found once in our laboratory homozygous in a 7-year-old male with severe intellectual disability, hypotonia, … (more)
This mutation has been previously reported as disease-causing and was found once in our laboratory homozygous in a 7-year-old male with severe intellectual disability, hypotonia, progressive dystonia, dysmorphism, microcephaly, progressive contractures, failure to thrive, and a similarly affected sibling (less)
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Pathogenic
(Jan 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611264.2
First in ClinVar: Oct 05, 2015 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Mar 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321607.8
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
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: 23284067, … (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: 23284067, 8147499, 22544365, 24524299, 23564332, 27777260, 25533962, 28687512, 11110791, 25326635, 30950035, 31692161, 30986545, 23975261, 31130284, 31980526, 33462000, 32645003, 31589614, 33163565, 33144682) (less)
|
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Pathogenic
(Dec 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
biparental
|
Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV003845235.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Clinical Features:
Abnormal hip bone morphology (present) , Absent speech (present) , Anteverted nares (present) , Astigmatism (present) , Broad hallux (present) , Broad thumb (present) , … (more)
Abnormal hip bone morphology (present) , Absent speech (present) , Anteverted nares (present) , Astigmatism (present) , Broad hallux (present) , Broad thumb (present) , Central hypotonia (present) , Coarse facial features (present) , Cognitive impairment (present) , Depressed nasal bridge (present) , Exotropia (present) , Failure to thrive (present) , Frontal bossing (present) , Generalized hypotonia (present) , Global developmental delay (present) , Hyperreflexia (present) , Hypertonia (present) , Hypoplastic philtrum (present) , Intellectual disability (present) , Limb hypertonia (present) , Lower limb asymmetry (present) , Microcephaly (present) , Micrognathia (present) , Myoclonus (present) , Osteopenia (present) , Profound global developmental delay (present) , Respiratory failure (present) , Retrocerebellar cyst (present) , Short stature (present) , Muscular atrophy (present) , Spastic paraplegia (present) , Triangular face (present) , Upslanted palpebral fissure (present) (less)
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: not provided
|
Pontocerebellar hypoplasia type 1B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004171134.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
|
|
Pathogenic
(Jul 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022230.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Dec 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001441091.2
First in ClinVar: Oct 31, 2020 Last updated: Feb 14, 2024 |
Comment:
Criteria applied: PM3_VSTR,PS3_SUP,PM2_SUP,PP3
Clinical Features:
Intellectual disability, severe (present) , Cerebellar ataxia (present) , Cerebellar hypoplasia (present) , Language disorder (present)
Sex: female
|
|
Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Pontocerebellar hypoplasia type 1B
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001375278.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 132 of the EXOSC3 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 132 of the EXOSC3 protein (p.Asp132Ala). This variant is present in population databases (rs141138948, gnomAD 0.07%). This missense change has been observed in individuals with pontocerebellar hypoplasia (PMID: 22544365, 23975261, 24524299, 25533962). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31688). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EXOSC3 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on EXOSC3 function (PMID: 22544365, 27777260, 28687512). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000244128.9
First in ClinVar: Sep 14, 2015 Last updated: May 01, 2024 |
Comment:
The c.395A>C (p.D132A) alteration is located in exon 2 (coding exon 2) of the EXOSC3 gene. This alteration results from an A to C substitution … (more)
The c.395A>C (p.D132A) alteration is located in exon 2 (coding exon 2) of the EXOSC3 gene. This alteration results from an A to C substitution at nucleotide position 395, causing the aspartic acid (D) at amino acid position 132 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD), the EXOSC3 c.395A>C alteration was observed in 0.04% (115/282766) of total alleles studied, with a frequency of 0.07% (94/129130) in the European (non-Finnish) subpopulation. The c.395A>C (p.D132A) alteration is the most common cause of EXOSC3-related pontocerebellar hypoplasia. This mutation has been reported in multiple affected individuals in the homozygous or compound heterozygous state (Wan, 2012; Biancheri, 2013; Eggens, 2014). The p.D132A alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 1B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV003921978.2
First in ClinVar: May 06, 2023 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pontocerebellar hypoplasia, type 1B (MIM#614678). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to alanine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (115 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (9 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated RNA binding S1 domain (PMID: 22544365). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and likely pathogenic, and has been reported in many homozygous and compound heterozygous patients with pontocerebellar hypoplasia (ClinVar, PMID: 22544365). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Apr 22, 2014)
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no assertion criteria provided
Method: literature only
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Pontocerebellar hypoplasia, type 1b
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000189382.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
Clinical Features:
Children homozygous for the pathogenic variant c.395A> (present) , C (p.Asp132Ala) could be described as having a relatively ‘mild’ clinical course. (present)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926523.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957993.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974917.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(Nov 01, 2013)
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no assertion criteria provided
Method: literature only
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PONTOCEREBELLAR HYPOPLASIA, TYPE 1B
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000045659.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 27, 2015 |
Comment on evidence:
In 4 brothers from a family of American and European ancestry with pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified a homozygous … (more)
In 4 brothers from a family of American and European ancestry with pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified a homozygous 395A-C transversion in exon 2 of the EXOSC3 gene, resulting in an asp132-to-ala (D132A) substitution in a highly conserved residue in the putative RNA-binding S1 domain, which may be important for intersubunit interaction within the exosome complex. The mutation was identified by genomewide scan and exome sequencing, and confirmed by Sanger sequencing. Sequencing of this gene identified the same homozygous mutation in affected individuals from 3 additional families with the disorder; 2 of these families were consanguineous. Haplotype analysis of 3 of the families with a homozygous D132A mutation was consistent with a remote common ancestor. Affected individuals in 3 additional families carried the D132A mutation in compound heterozygosity with another pathogenic mutation in the EXOSC3 gene (see, e.g., 606489.0002 and 606489.0003). All available parents were unaffected and heterozygous for 1 of the mutations, which were not found in 379 control individuals. The phenotype consisted of neonatal onset of severe hypotonia, often with respiratory insufficiency, and global developmental delay, without achieving any motor milestones or speech, and progressive microcephaly. Other features included oculomotor apraxia, progressive muscle wasting, and distal contractures. Brain MRI showed marked cerebellar and pontine atrophy. Postmortem examination showed severe loss of cerebellar and spinal motor neurons. In 2 teenaged sibs of Bangladeshi descent with PCH1B, Zanni et al. (2013) identified compound heterozygous mutations in the EXOSC3 gene: D132A, and a c.238G-T transversion, resulting in a val80-to-phe (V80F; 606489.0006) substitution at a conserved residue in the N-terminal domain. The mutations were found by exome sequencing and filtered against the dbSNP (build 135) and 1000 Genomes Project databases; D132A was observed in 6 of 4,870 control exomes (allele frequency of 0.0012). The unaffected parents and 2 unaffected sibs were heterozygous for 1 of the mutations. Functional studies of the variants were not performed. The patients had a relatively mild form of the disorder, with delayed motor development, onset of spasticity in childhood, and mild to moderate intellectual disability, but without hypotonia or microcephaly. The report expanded the phenotypic spectrum associated with EXOSC3 mutations to include hereditary spastic paraplegia. (less)
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Pathogenic
(Apr 05, 2016)
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no assertion criteria provided
Method: research
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Pontocerebellar hypoplasia type 1B
Affected status: yes
Allele origin:
germline
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536754.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel EXOSC3 pathogenic variant results in a mild course of neurologic disease with cerebellum involvement. | Le Duc D | European journal of medical genetics | 2020 | PMID: 30986545 |
EXOSC3 Pontocerebellar Hypoplasia. | Adam MP | - | 2020 | PMID: 25144110 |
Pontocerebellar hypoplasia type 1 for the neuropediatrician: Genotype-phenotype correlations and diagnostic guidelines based on new cases and overview of the literature. | Ivanov I | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2018 | PMID: 29656927 |
The recurrent mutation in TMEM106B also causes hypomyelinating leukodystrophy in China and is a CpG hotspot. | Yan H | Brain : a journal of neurology | 2018 | PMID: 29444210 |
A recurrent de novo mutation in TMEM106B causes hypomyelinating leukodystrophy. | Simons C | Brain : a journal of neurology | 2017 | PMID: 29186371 |
Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia. | Schottmann G | Mitochondrion | 2017 | PMID: 28687512 |
Insight into the RNA Exosome Complex Through Modeling Pontocerebellar Hypoplasia Type 1b Disease Mutations in Yeast. | Fasken MB | Genetics | 2017 | PMID: 27777260 |
Utility of whole exome sequencing for the early diagnosis of pediatric-onset cerebellar atrophy associated with developmental delay in an inbred population. | Megahed H | Orphanet journal of rare diseases | 2016 | PMID: 27146152 |
Large-scale discovery of novel genetic causes of developmental disorders. | Deciphering Developmental Disorders Study | Nature | 2015 | PMID: 25533962 |
Novel EXOSC3 mutation causes complicated hereditary spastic paraplegia. | Halevy A | Journal of neurology | 2014 | PMID: 25149867 |
Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. | Peeters K | Brain : a journal of neurology | 2014 | PMID: 24970098 |
EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations. | Eggens VR | Orphanet journal of rare diseases | 2014 | PMID: 24524299 |
Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3. | Zanni G | Neurogenetics | 2013 | PMID: 23975261 |
Homozygous EXOSC3 mutation c.92G→C, p.G31A is a founder mutation causing severe pontocerebellar hypoplasia type 1 among the Czech Roma. | Schwabova J | Journal of neurogenetics | 2013 | PMID: 23883322 |
EXOSC3 mutations in isolated cerebellar hypoplasia and spinal anterior horn involvement. | Biancheri R | Journal of neurology | 2013 | PMID: 23564332 |
Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. | Wan J | Nature genetics | 2012 | PMID: 22544365 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EXOSC3 | - | - | - | - |
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Text-mined citations for rs141138948 ...
HelpRecord last updated Sep 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.