ClinVar Genomic variation as it relates to human health
NM_007055.4(POLR3A):c.1909+22G>A
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
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NM_007055.4(POLR3A):c.1909+22G>A
Variation ID: 445922 Accession: VCV000445922.83
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q22.3 10: 79769273 (GRCh37) [ NCBI UCSC ] 10: 78009515 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Nov 5, 2017 May 12, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007055.4:c.1909+22G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000010.11:g.78009515C>T NC_000010.10:g.79769273C>T NG_029648.1:g.25026G>A - Protein change
- Other names
- -
- Canonical SPDI
- NC_000010.11:78009514:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00060 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00094
Exome Aggregation Consortium (ExAC) 0.00133
The Genome Aggregation Database (gnomAD), exomes 0.00137
Trans-Omics for Precision Medicine (TOPMed) 0.00150
The Genome Aggregation Database (gnomAD) 0.00156
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00277
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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POLR3A | - | - |
GRCh38 GRCh37 |
1013 | 1153 |
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. |
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Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000514925.37 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 30, 2023 | RCV000754390.16 | |
Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2024 | RCV000988394.24 | |
POLR3A-related neurological disorders
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Pathogenic (1) |
criteria provided, single submitter
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Mar 2, 2020 | RCV001249723.12 |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Feb 7, 2023 | RCV001814996.12 | |
POLR3A-related disorder
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 20, 2024 | RCV002448556.10 |
not provided (1) |
no classification provided
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- | RCV002506245.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 7, 2021 | RCV002528232.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 24, 2023 | RCV003403205.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 1, 2022 | RCV003993993.1 |
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
(Jun 02, 2017)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610762.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
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Likely pathogenic
(May 01, 2018)
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criteria provided, single submitter
Method: research
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Neonatal pseudo-hydrocephalic progeroid syndrome
Affected status: yes
Allele origin:
germline
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Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital
Accession: SCV000786641.1
First in ClinVar: Jan 26, 2019 Last updated: Jan 26, 2019 |
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138096.1
First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020 |
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Pathogenic
(Oct 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001134970.1
First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020 |
Comment:
Identified in multiple unrelated patients with POLR3A-related disorders tested at GeneDx and in the published literature who had different pathogenic variants on the opposite allele … (more)
Identified in multiple unrelated patients with POLR3A-related disorders tested at GeneDx and in the published literature who had different pathogenic variants on the opposite allele (La Piana et al., 2016; Minnerop et al., 2017; Travaglini et al., 2018) Functional studies suggest this variant generates a "leaky" cryptic donor site that results in the inclusion of part of intron 14 (Minnerop et al., 2017) In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect Observed in 0.1365% (386/282828 alleles) in large population cohorts (Lek et al., 2016). (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446415.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Cerebellar ataxia (present)
Sex: female
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Pathogenic
(Jan 04, 2021)
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criteria provided, single submitter
Method: research
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Neonatal pseudo-hydrocephalic progeroid syndrome
Affected status: yes
Allele origin:
inherited
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Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris
Accession: SCV001519178.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
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Pathogenic
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557627.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
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 leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism (MIM#607694), Wiedemann-Rautenstrauch syndrome (MIM#264090) and POLR3A-related spastic ataxia (PMID: 31637490). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Functional analysis of patient leucocyte-derived cDNA, has demonstrated that this variant results in the leaky inclusion of 19 nucleotides in intron 14. This results in a shift in the reading frame, and the production of a protein with a premature termination codon (p.Tyr637Cysfs*14), shown to be degraded by nonsense mediated decay (PMID: 28459997). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (386 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant as been reported many times as pathogenic, and has been observed in at least 30 compound heterozygous individuals with limb and gait ataxia (ClinVar). It has also been observed in a homozygous individual with childhood-onset axonal neuropathy (PMID: 28459997), and segregated in another family with spastic ataxia and hypodontia, who had an additional pathogenic splice variant in cis (PMID: 33491183). (SP) 1207 - Parental origin of the variant is unresolved (by quad analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Nov 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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POLR3A-related disorders
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Variantyx, Inc.
Accession: SCV002754528.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
This is a non-canonical splice variant in the POLR3A gene (OMIM 614258). Biallelic pathogenic variants in this gene have been associated with autosomal recessive POLR3A-related … (more)
This is a non-canonical splice variant in the POLR3A gene (OMIM 614258). Biallelic pathogenic variants in this gene have been associated with autosomal recessive POLR3A-related disorders. Functional studies demonstrate that this variant disrupts mRNA splicing leading to premature termination and nonsense-mediated mRNA decay (PMID: 28459997, 30323018) (PVS1). This variant has been reported in the homozygous or compound heterozygous state in many unrelated affected individuals (PMID: 28459997, 29691679, 30847471, 31637490) (PM3_Very Strong). This variant has been observed to segregate with disease in multiple affected families (PMID: 30847471, 31637490) (PP1_Strong). This variant has a 0.2763 % maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal recessive POLR3A-related disorders. (less)
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Pathogenic
(Mar 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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POLR3A-related neurological disorders
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV001423749.2
First in ClinVar: Jul 27, 2020 Last updated: Mar 04, 2023 |
Comment:
The POLR3A c.1909+22G>A variant is an intronic variant. Across a selection of the available literature, the c.1909+22G>A variant has been identified in at least 30 … (more)
The POLR3A c.1909+22G>A variant is an intronic variant. Across a selection of the available literature, the c.1909+22G>A variant has been identified in at least 30 unrelated individuals in a compound heterozygous state, all presenting with limb and gait ataxia. Tremor in the upper and lower limbs, dental problems, myopia, dysarthria, and dysphagia were also noted in some of these individuals. In addition, brain MRIs showed hyperintensities along the cerebellar peduncles, cervical cord atrophy, and hypoplasia of the corpus callosum (Minnerop et al. 2017; Rydning et al. 2019; Infante et al. 2020). Mild hypomyelination was also observed in some affected individuals (Rydning et al. 2019). The c.1909+22G>A variant was also present one individual in a homozygous state, primarily presenting with childhood-onset axonal neuropathy, in addition to gait ataxia (Minnerop et al. 2017). At least seven families had multiple affected individuals with the variant in a compound heterozygous state (Minnerop et al. 2017; Rydning et al. 2019; Infante et al. 2020). Evaluation of PCR products from affected individuals and healthy controls indicated that the variant affects splicing of exon 14, although this effect may be incomplete. In addition, inhibition of nonsense medicated mRNA decay in fibroblasts from affected individuals suggested the aberrantly spliced transcript due to the c.1909+22G>A variant is subject to nonsense mediated decay. In addition, gene and protein expression were reduced in the presence of the variant compared to controls (Minnerop et al. 2017). The c.1909+22G>A variant is reported at a frequency of 0.002238 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the c.1909+22G>A variant is classified as pathogenic for POLR3A-related neurological disorders. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Neonatal pseudo-hydrocephalic progeroid syndrome
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003841199.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
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Pathogenic
(Apr 27, 2023)
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criteria provided, single submitter
Method: research
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POLR3A-related disorders
Affected status: yes
Allele origin:
germline
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Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)
Accession: SCV003920806.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Number of individuals with the variant: 3
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV004013835.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The intronic variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.136%). Although in silico tools do not … (more)
The intronic variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.136%). Although in silico tools do not predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.10), a study showed that alternative splicing having the first 19 nucleotides of intron 14 included in the transcript resulted in a shift of the reading frame (PMID: 28459997). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 28459997, 30323018, 30847471). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the the same family or similarly affected unrelated family (PMID: 28459997). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000445922/PMID: 27029625). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Intellectual disability (present) , Cognitive impairment (present) , Mental deterioration (present) , Mental deterioration (present) , Global developmental delay (present) , Global developmental delay (present) … (more)
Intellectual disability (present) , Cognitive impairment (present) , Mental deterioration (present) , Mental deterioration (present) , Global developmental delay (present) , Global developmental delay (present) , Intellectual disability (present) , Rapidly progressive (present) , Aggressive behavior (present) , Aggressive behavior (present) , Excessive salivation (present) , Self-biting (present) , Memory impairment (present) , Absent speech (present) , Absent speech (present) (less)
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Pathogenic
(Aug 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045822.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present) , Myoclonus (present) , Tremor (present)
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Pathogenic
(Oct 24, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Pol III-related leukodystrophy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122078.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: POLR3A c.1909+22G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: … (more)
Variant summary: POLR3A c.1909+22G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: One predict the variant weakens a canonical 5' donor site. Three predict the variant strengthens a cryptic 5' donor site. Functional studies suggest this variant activates a "leaky" cryptic donor site that results in the inclusion of part of intron 14, and the production of a protein with a premature termination codon (p.Tyr637Cysfs*14), shown to be degraded by nonsense mediated decay (Minnerop_2017, Paolacci_ 2018). c.1909+22G>A has been reported in the literature in homozygous state and in trans with a loss of function alteration in multiple unrelated patients affected with autosomal recessive spastic ataxic phenotype (Minnerop_ 2017). Additionally, it has also been reported in individuals affected with leukodystrophy (Macken_ 2022) and Wiedemann-Rautenstrauch syndrome (Paolacci_ 2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28459997, 30323018, 36344503). Eighteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=15) as well as uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neonatal pseudo-hydrocephalic progeroid syndrome
Affected status: no
Allele origin:
unknown
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000930453.2
First in ClinVar: Aug 04, 2019 Last updated: Jan 06, 2024 |
Geographic origin: Iran
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Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: curation
|
Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV004232684.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The c.1909+22G>A variant in POLR3A has been reported in >10 individuals with POLR3A-related disorders (PMID: 28459997, 30323018), segregated with disease in 4 affected relatives from … (more)
The c.1909+22G>A variant in POLR3A has been reported in >10 individuals with POLR3A-related disorders (PMID: 28459997, 30323018), segregated with disease in 4 affected relatives from 2 families (PMID: 28459997), and has been identified in 0.2% (289/129138) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs191875469). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 445922) and has been interpreted as likely pathogenic or pathogenic by multiple laboratories, as well as a variant of uncertain significance by a few additional labs. Of the 18 affected individuals, 1 of those was a homozygote and 8 were compound heterozygotes that carried reported pathogenic and likely pathogenic variants in trans or with unknown phase, which increases the likelihood that the c.1909+22G>A variant is pathogenic (VariationID: 684773; PMID: 28459997). In vitro functional studies provide some evidence that the c.1909+22G>A variant may impact protein function (PMID: 28459997). However, these types of assays may not accurately represent biological function. This variant is located in the 3’ splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. This variant was also detected in 1 homozygous and supposedly unaffected Palestinian individual (PMID:30323018). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PS3_moderate, PM3_strong, PP1_strong (Richards 2015). (less)
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019479.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001583974.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 14 of the POLR3A gene. It does not directly change the encoded amino acid sequence of the POLR3A protein. … (more)
This sequence change falls in intron 14 of the POLR3A gene. It does not directly change the encoded amino acid sequence of the POLR3A protein. This variant is present in population databases (rs191875469, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with clinical features of POLR3A-related leukodystrophies (PMID: 27029625, 28459997, 29691679, 30323018, 30847471, 31637490). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 445922). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28459997, 30323018). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 20, 2024)
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criteria provided, single submitter
Method: clinical testing
|
POLR3A-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004116147.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The POLR3A c.1909+22G>A variant is predicted to interfere with splicing. This variant has been reported in the homozygous and compound heterozygous states in multiple families … (more)
The POLR3A c.1909+22G>A variant is predicted to interfere with splicing. This variant has been reported in the homozygous and compound heterozygous states in multiple families with variable-onset ataxia with or without tremor (La Piana et al. 2016. PubMed ID: 27029625; Minnerop et al. 2017. PubMed ID: 28459997; Travaglini et al. 2018. PubMed ID: 29691679; D'Amore et al. 2018. PubMed ID: 30564185; Paolacci et al. 2018. PubMed ID: 30323018; Rydning et al. 2019. PubMed ID: 30847471; Infante et al. 2020. PubMed ID: 31637490; de Assis Pereira Matos et al. 2020. PubMed ID: 32373668; Ruggiero et al. 2020. PubMed ID: 33085208). Additional studies indicate that the c.1909+22G>A variant, which is postulated to be a hypomorphic variant, generates a novel cryptic splice donor site, leading to a frameshift and premature protein termination; the resulting transcript is subject to nonsense-mediated mRNA decay (Minnerop et al. 2017. PubMed ID: 28459997). The c.1909+22G>A variant is reported at a minor allele frequency of up to ~0.22% in one large continental population but is not reported in the homozygous state. Based on the available evidence, we classify the c.1909+22G>A variant as likely pathogenic. (less)
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Likely pathogenic
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807190.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Apr 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Spastic ataxia
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812517.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in POLR3A is an intronic variant located in intron 14. The highest population minor allele frequency in gnomAD v2.1 is 0.2% (289/129,138 … (more)
This sequence change in POLR3A is an intronic variant located in intron 14. The highest population minor allele frequency in gnomAD v2.1 is 0.2% (289/129,138 alleles) in the European (non-Finnish) population. This variant has been detected homozygous or compound heterozygous with a second allele in at least 19 individuals with spastic ataxia with/without dental abnormalities, segregating with disease in at least two of these families (PMID: 28459997). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, NNSplice) are conflicting on whether this variant may impact splicing by creation of a de novo donor splice site of intron 14 of POLR3A. This prediction is confirmed by RT-PCR. The assay demonstrated that the variant impacts splicing by activation of a leaky cryptic donor site leading to 19 bp intron 14 inclusion (p.Tyr637Cysfs*14). The variant has been described as a hypomorph, because it leads to leaky cryptic donor activation and is not associated with the classic POLR3A-related leukodystrophy phenotype (PMID: 28459997). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PS3_Supporting. (less)
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Pathogenic
(Oct 07, 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: SCV003718066.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1909+22G>A intronic alteration results from a G to A substitution 22 nucleotides after coding exon 14 of the POLR3A gene. The c.1909+22G>A alteration is … (more)
The c.1909+22G>A intronic alteration results from a G to A substitution 22 nucleotides after coding exon 14 of the POLR3A gene. The c.1909+22G>A alteration is a hypomorphic allele that has been reported in the homozygous state and in trans with a second loss of function alteration in multiple unrelated patients with an autosomal recessive spastic ataxic phenotype with mild dental involvement and hyperintensities along the superior cerebellar peduncles (Minnerop, 2017; Rydning, 2019; Morales-Rosado, 2020; de Assis Pereira Matos, 2020). This alteration has been shown to cosegregate with disease in one family with four affected siblings (Minnerop, 2017). In a case-control study, the c.1909+22G>A variant was significantly associated (P = 1.3 x 10-4, odds ratio = 3.11) with hereditary spastic paraplegia, cerebellar ataxia, and/or neuropathy cases compared to other disease phenotypes and healthy controls (Minnerop, 2017). In addition, the c.1909+22G>A alteration has been reported in cis with c.3337-11T>C in several patients with Wiedemann-Rautenstrauch syndrome who carried this complex allele in trans with a second loss of function alteration (Paolacci, 2018). This nucleotide position is not well conserved in available vertebrate species. Functional RNA studies of c.1909+22G>A demonstrated a mild effect on splicing due to activation of an out of frame cryptic splice site which resulted in partial intron 14 retention and a transcript that was partially degraded by nonsense mediated decay (Minnerop, 2017; Rydning, 2019; Morales-Rosado, 2020). RNA studies in two patients who harbored the complex allele [c.1909+22G>A; c.3337-11T>C] demonstrated that both variants resulted in aberrant splicing and thus the additive effect on splicing was proposed to be a greater loss of function allele associated with a more severe phenotype (Paolacci, 2018). In addition, another variant affecting the same splice site (c.1909+18G>A) also demonstrated aberrant splicing on functional studies (Bernard, 2011). In silico splice site analysis for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jan 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247298.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
POLR3A: PM3:Very Strong, PP1:Strong, PM2, PS3:Supporting
Number of individuals with the variant: 16
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760259.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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Likely 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: SCV001927538.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely 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: SCV001972286.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Likely pathogenic
(Apr 01, 2023)
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no assertion criteria provided
Method: clinical testing
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Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
Affected status: yes
Allele origin:
germline
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Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927902.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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not provided
(-)
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no classification provided
Method: literature only
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Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV001760626.2
First in ClinVar: Jul 24, 2021 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism Neonatal pseudo-hydrocephalic progeroid syndrome
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002817113.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
Variant classified as Pathogenic and reported on 09-15-2021 by Lab or GTR ID 506526. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant classified as Pathogenic and reported on 09-15-2021 by Lab or GTR ID 506526. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Muscle weakness (present) , Limb-girdle muscle weakness (present) , Tremor (present) , Lower limb muscle weakness (present) , Paresthesia (present) , Gait ataxia (present) , … (more)
Muscle weakness (present) , Limb-girdle muscle weakness (present) , Tremor (present) , Lower limb muscle weakness (present) , Paresthesia (present) , Gait ataxia (present) , Cerebellar ataxia (present) , Sensory neuropathy (present) (less)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: male
Method: Genome Sequencing
Testing laboratory: Variantyx, Inc.
Date variant was reported to submitter: 2021-09-15
Testing laboratory interpretation: Pathogenic
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Uncertain significance
(Sep 25, 2019)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Unnecessary conflicting claim for distinct condition when other classifications are more relevant
Source: ClinGen
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Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001521993.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Uncertain significance
(May 30, 2018)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002061954.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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 |
---|---|---|---|---|
Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing. | Macken WL | Nature communications | 2022 | PMID: 36344503 |
Two intronic cis-acting variants in both alleles of the POLR3A gene cause progressive spastic ataxia with hypodontia. | Fellner A | Clinical genetics | 2021 | PMID: 33491183 |
Interpretation challenges of novel dual-class missense and splice-impacting variant in POLR3A-related late-onset hereditary spastic ataxia. | Morales-Rosado JA | Molecular genetics & genomic medicine | 2020 | PMID: 32597037 |
POLR3A-Related Disorder Presenting with Late-Onset Dystonia and Spastic Paraplegia. | de Assis Pereira Matos PCA | Movement disorders clinical practice | 2020 | PMID: 32373668 |
POLR3A-related spastic ataxia: new mutations and a look into the phenotype. | Infante J | Journal of neurology | 2020 | PMID: 31637490 |
Biallelic POLR3A variants confirmed as a frequent cause of hereditary ataxia and spastic paraparesis. | Rydning SL | Brain : a journal of neurology | 2019 | PMID: 30847471 |
Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome. | Paolacci S | Journal of medical genetics | 2018 | PMID: 30323018 |
The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes. | Travaglini L | Neurogenetics | 2018 | PMID: 29691679 |
Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia. | Minnerop M | Brain : a journal of neurology | 2017 | PMID: 28459997 |
Wiedemann-Rautenstrauch syndrome: A phenotype analysis. | Paolacci S | American journal of medical genetics. Part A | 2017 | PMID: 28447407 |
Diffuse hypomyelination is not obligate for POLR3-related disorders. | La Piana R | Neurology | 2016 | PMID: 27029625 |
Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. | Bernard G | American journal of human genetics | 2011 | PMID: 21855841 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c3d137e0-3f53-488a-a0ee-c29ced42e510 | - | - | - | - |
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Text-mined citations for rs191875469 ...
HelpRecord last updated Jun 02, 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.