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; This variant is associated with the following publications: (PMID: 28459997, 27612211, 31589614)
ClinVar Genomic variation as it relates to human health
NM_007055.4(POLR3A):c.2617C>T (p.Arg873Ter)
Germline
Classification
Help
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.
(8)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007055.4(POLR3A):c.2617C>T (p.Arg873Ter)
Variation ID: 235466 Accession: VCV000235466.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q22.3 10: 77993367 (GRCh38) [ NCBI UCSC ] 10: 79753125 (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 Jun 9, 2016 Oct 20, 2024 Jan 4, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007055.4:c.2617C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_008986.2:p.Arg873Ter nonsense NM_007055.3:c.2617C>T NC_000010.11:g.77993367G>A NC_000010.10:g.79753125G>A NG_029648.1:g.41174C>T - Protein change
- R873*
- Other names
-
NM_007055.4(POLR3A):c.2617C>T
p.Arg873Ter
- Canonical SPDI
- NC_000010.11:77993366: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| POLR3A | - | - |
GRCh38 GRCh37 |
1035 | 1175 | |
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 (1) |
no assertion criteria provided
|
Feb 13, 2019 | RCV000755662.1 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 4, 2024 | RCV000224488.21 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 24, 2023 | RCV002516224.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2022 | RCV004532823.1 |
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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|---|---|---|---|---|---|
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Pathogenic
(Nov 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002757567.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
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 disease; This … (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; This variant is associated with the following publications: (PMID: 28459997, 27612211, 31589614) (less)
|
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Pathogenic
(Jan 24, 2023)
|
criteria provided, single submitter
Method: curation
|
Leukodystrophy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761130.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Arg873Ter variant in POLR3A has been reported in 2 individuals with POLR3A-related disorders (PMID: 27612211, 28459997), and has been identified in 0.01% (2/19914) of … (more)
The p.Arg873Ter variant in POLR3A has been reported in 2 individuals with POLR3A-related disorders (PMID: 27612211, 28459997), and has been identified in 0.01% (2/19914) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs148932047). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 235466) and has been interpreted as pathogenic by Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics), Invitae, OMIM, and PerkinElmer Genomics. Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Arg873Ter variant is pathogenic (VariationID: 31144; PMID: 27612211). This nonsense variant leads to a premature termination codon at position 873, 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, this variant meets criteria to be classified as pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015). (less)
|
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Pathogenic
(Sep 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019476.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Jan 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002229938.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg873*) in the POLR3A gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg873*) 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). This variant is present in population databases (rs148932047, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neonatal progeriod syndrome and/or spastic ataxia (PMID: 27612211, 28459997). ClinVar contains an entry for this variant (Variation ID: 235466). For these reasons, this variant has been classified as Pathogenic. (less)
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|
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Pathogenic
(Oct 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
POLR3A-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004109207.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The POLR3A c.2617C>T variant is predicted to result in premature protein termination (p.Arg873*). This variant has been reported in the compound heterozygous state in two … (more)
The POLR3A c.2617C>T variant is predicted to result in premature protein termination (p.Arg873*). This variant has been reported in the compound heterozygous state in two individuals with autosomal recessive POLR3A related disorders (Jay et al. 2016. PubMed ID: 27612211; Minnerop et al. 2017. PubMed ID: 28459997). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-79753125-G-A). Nonsense variants in POLR3A are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
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Pathogenic
(Oct 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004125824.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
POLR3A: PVS1, PM3:Strong, PM2
Number of individuals with the variant: 1
|
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Pathogenic
(Jan 08, 2016)
|
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: SCV000281068.1
First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016 |
|
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Pathogenic
(Feb 13, 2019)
|
no assertion criteria provided
Method: literature only
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WIEDEMANN-RAUTENSTRAUCH SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000883061.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment on evidence:
For discussion of the c.2617C-T transition in exon 20 of the POLR3A gene, resulting in an arg873-to-ter (R873X) substitution, that was found in compound heterozygous … (more)
For discussion of the c.2617C-T transition in exon 20 of the POLR3A gene, resulting in an arg873-to-ter (R873X) substitution, that was found in compound heterozygous state in a female infant with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Jay et al. (2016), see 614258.0002. (less)
|
Comment:
Comment:
The p.Arg873Ter variant in POLR3A has been reported in 2 individuals with POLR3A-related disorders (PMID: 27612211, 28459997), and has been identified in 0.01% (2/19914) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs148932047). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 235466) and has been interpreted as pathogenic by Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics), Invitae, OMIM, and PerkinElmer Genomics. Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Arg873Ter variant is pathogenic (VariationID: 31144; PMID: 27612211). This nonsense variant leads to a premature termination codon at position 873, 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, this variant meets criteria to be classified as pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015).
Comment:
This sequence change creates a premature translational stop signal (p.Arg873*) 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). This variant is present in population databases (rs148932047, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neonatal progeriod syndrome and/or spastic ataxia (PMID: 27612211, 28459997). ClinVar contains an entry for this variant (Variation ID: 235466). For these reasons, this variant has been classified as Pathogenic.
Comment:
The POLR3A c.2617C>T variant is predicted to result in premature protein termination (p.Arg873*). This variant has been reported in the compound heterozygous state in two individuals with autosomal recessive POLR3A related disorders (Jay et al. 2016. PubMed ID: 27612211; Minnerop et al. 2017. PubMed ID: 28459997). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-79753125-G-A). Nonsense variants in POLR3A are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
POLR3A: PVS1, PM3:Strong, PM2
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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; This variant is associated with the following publications: (PMID: 28459997, 27612211, 31589614)
Comment:
The p.Arg873Ter variant in POLR3A has been reported in 2 individuals with POLR3A-related disorders (PMID: 27612211, 28459997), and has been identified in 0.01% (2/19914) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs148932047). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 235466) and has been interpreted as pathogenic by Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics), Invitae, OMIM, and PerkinElmer Genomics. Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Arg873Ter variant is pathogenic (VariationID: 31144; PMID: 27612211). This nonsense variant leads to a premature termination codon at position 873, 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, this variant meets criteria to be classified as pathogenic for autosomal recessive POLR3A-related disorders. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015).
Comment:
This sequence change creates a premature translational stop signal (p.Arg873*) 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). This variant is present in population databases (rs148932047, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neonatal progeriod syndrome and/or spastic ataxia (PMID: 27612211, 28459997). ClinVar contains an entry for this variant (Variation ID: 235466). For these reasons, this variant has been classified as Pathogenic.
Comment:
The POLR3A c.2617C>T variant is predicted to result in premature protein termination (p.Arg873*). This variant has been reported in the compound heterozygous state in two individuals with autosomal recessive POLR3A related disorders (Jay et al. 2016. PubMed ID: 27612211; Minnerop et al. 2017. PubMed ID: 28459997). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-79753125-G-A). Nonsense variants in POLR3A are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
POLR3A: PVS1, PM3:Strong, PM2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia. | Minnerop M | Brain : a journal of neurology | 2017 | PMID: 28459997 |
| 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 rs148932047 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.