ClinVar Genomic variation as it relates to human health
NM_007055.4(POLR3A):c.760C>T (p.Arg254Ter)
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.760C>T (p.Arg254Ter)
Variation ID: 617894 Accession: VCV000617894.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q22.3 10: 78022270 (GRCh38) [ NCBI UCSC ] 10: 79782028 (GRCh37) [ 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 Feb 18, 2019 Jun 17, 2024 Aug 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007055.4:c.760C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_008986.2:p.Arg254Ter nonsense NC_000010.11:g.78022270G>A NC_000010.10:g.79782028G>A NG_029648.1:g.12271C>T - Protein change
- R254*
- Other names
- NM_007055.4(POLR3A):c.760C>T
- p.Arg254Ter
- Canonical SPDI
- NC_000010.11:78022269:G:A
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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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
1015 | 1155 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (3) |
criteria provided, single submitter
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Oct 1, 2018 | RCV000755671.6 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2023 | RCV000994469.26 | |
Wiedemann-Rautenstrauch-like progeroid syndrome
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Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001291256.2 |
not provided (1) |
no classification provided
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- | RCV002507319.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 11, 2023 | RCV003330936.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002533777.3 |
Submissions - Germline
Classification
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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
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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
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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
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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
(Oct 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:
inherited
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Cole/Wambach Lab, Washington University in St. Louis
Accession: SCV000886476.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019
Comment:
in trans with c.3337-5T>A
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Number of individuals with the variant: 1
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Pathogenic
(Jan 25, 2023)
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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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Invitae
Accession: SCV002135625.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 617894). This premature translational stop signal has been observed in individual(s) with Wiedemann-Rautenstrauch syndrome (PMID: 30414627, 30450527). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs141659018, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg254*) in the POLR3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLR3A are known to be pathogenic (PMID: 21855841, 25339210, 27612211, 30414627, 30450527). (less)
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Likely pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: curation
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Leukoencephalopathy-ataxia-hypodontia-hypomyelination syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761141.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Arg254Ter variant in POLR3A has been reported in 1 individual, in the compound heterozygous state, with POLR3A-related disorders (PMID: 30450527, 30414627) and has been … (more)
The p.Arg254Ter variant in POLR3A has been reported in 1 individual, in the compound heterozygous state, with POLR3A-related disorders (PMID: 30450527, 30414627) and has been identified in 0.01% (3/24970) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs141659018). 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#: 617894) and has been interpreted as pathogenic or likely pathogenic by multiple laboratories. This nonsense variant leads to a premature termination codon at position 254, which is predicted to lead to a truncated or absent protein. Loss of function of the POLR3A gene is an established disease mechanism in autosomal recessive POLR3A-related disorders. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1, PM3 (Richards 2015). (less)
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Likely pathogenic
(Mar 01, 2018)
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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: SCV001148006.23
First in ClinVar: Feb 03, 2020 Last updated: Jun 17, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 01, 2022)
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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: SCV003930553.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 30414627, 30450527) (less)
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Pathogenic
(Aug 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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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: SCV004039082.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: POLR3A c.760C>T (p.Arg254X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is … (more)
Variant summary: POLR3A c.760C>T (p.Arg254X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2.4e-05 in 251396 control chromosomes. c.760C>T has been reported in the literature at a compound heterozygous state with a second pathogenic variant in at-least one individual affected with Wiedemann-Rautenstrauch Syndrome (example, Wambach_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. These data indicate that the variant is very likely associated with POLR3A-associated diseases including Wiedemann-Rautenstrauch Syndrome and Pol III-Related Leukodystrophy. The following publication has been ascertained in the context of this evaluation (PMID: 30414627). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 02, 2024)
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no assertion criteria provided
Method: literature only
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WIEDEMANN-RAUTENSTRAUCH SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000883073.3
First in ClinVar: Feb 18, 2019 Last updated: Apr 06, 2024 |
Comment on evidence:
For discussion of the c.760C-T transition in the POLR3A gene, resulting in an arg254-to-ter (R254X) substitution, that was found in compound heterozygosity in a 12.75-year-old … (more)
For discussion of the c.760C-T transition in the POLR3A gene, resulting in an arg254-to-ter (R254X) substitution, that was found in compound heterozygosity in a 12.75-year-old girl (patient 4) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Lessel et al. (2018), see 614258.0018. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Wiedemann-Rautenstrauch Syndrome
Affected status: yes
Allele origin:
inherited
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001479499.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Wiedemann-Rautenstrauch-like progeroid syndrome
Affected status: yes
Allele origin:
inherited
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001479681.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 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: SCV001959515.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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: SCV001972787.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002817114.2
First in ClinVar: Dec 31, 2022 Last updated: Jun 17, 2024 |
Comment:
Variant classified as Likely pathogenic and reported on 09-15-2021 by Lab or GTR ID 506526. GenomeConnect assertions are reported exactly as they appear on the … (more)
Variant classified as Likely 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: Likely pathogenic
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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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Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations. | Lessel D | Human genetics | 2018 | PMID: 30450527 |
Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome. | Wambach JA | American journal of human genetics | 2018 | PMID: 30414627 |
Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A. | Jay AM | American journal of medical genetics. Part A | 2016 | PMID: 27612211 |
Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations. | Wolf NI | Neurology | 2014 | PMID: 25339210 |
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 |
Text-mined citations for rs141659018 ...
HelpRecord last updated Jun 17, 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.