The p.Arg550Ter variant in POLR3B has been reported in 1 individual in the compound heterozygous state with 4H leukodystrophy (PMID: 22036171), and has been identified in 0.003% (1/34550) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267608688). 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#: 31162) and has been interpreted as pathogenic by GeneReviews and OMIM. In vitro functional studies provide some evidence that the p.Arg550Ter variant may impact protein function (PMID: 22036171). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 550, which is predicted to lead to a truncated or absent protein. Loss of function of the POLR3B gene is an established disease mechanism in autosomal recessive 4H leukodystrophy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive4H leukodystrophy. ACMG/AMP Criteria applied: PVS1, PS3_moderate, PM2_supporting (Richards 2015).
ClinVar Genomic variation as it relates to human health
NM_018082.6(POLR3B):c.1648C>T (p.Arg550Ter)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_018082.6(POLR3B):c.1648C>T (p.Arg550Ter)
Variation ID: 31162 Accession: VCV000031162.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q23.3 12: 106433739 (GRCh38) [ NCBI UCSC ] 12: 106827517 (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 Apr 4, 2013 Apr 15, 2023 Apr 22, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_018082.6:c.1648C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060552.4:p.Arg550Ter nonsense NM_001160708.2:c.1474C>T NP_001154180.1:p.Arg492Ter nonsense NC_000012.12:g.106433739C>T NC_000012.11:g.106827517C>T NG_031837.1:g.81082C>T - Protein change
- R550*, R492*
- Other names
-
NM_018082.6(POLR3B):c.1648C>T
p.Arg550Ter
p.R550*
- Canonical SPDI
- NC_000012.12:106433738:C:T
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
- 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. |
|||
| POLR3B | - | - |
GRCh38 GRCh37 |
451 | 581 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 21, 2022 | RCV000024158.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 22, 2022 | RCV002243660.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 24, 2022)
|
criteria provided, single submitter
Method: curation
|
Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761426.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Arg550Ter variant in POLR3B has been reported in 1 individual in the compound heterozygous state with 4H leukodystrophy (PMID: 22036171), and has been identified … (more)
The p.Arg550Ter variant in POLR3B has been reported in 1 individual in the compound heterozygous state with 4H leukodystrophy (PMID: 22036171), and has been identified in 0.003% (1/34550) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267608688). 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#: 31162) and has been interpreted as pathogenic by GeneReviews and OMIM. In vitro functional studies provide some evidence that the p.Arg550Ter variant may impact protein function (PMID: 22036171). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 550, which is predicted to lead to a truncated or absent protein. Loss of function of the POLR3B gene is an established disease mechanism in autosomal recessive 4H leukodystrophy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive4H leukodystrophy. ACMG/AMP Criteria applied: PVS1, PS3_moderate, PM2_supporting (Richards 2015). (less)
|
|
|
Pathogenic
(Apr 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002512891.2
First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect (cells expressing R550X failed to differentiate morphologically and phosphorylation/activation levels of molecules associated with mTOR signaling were decreased) … (more)
Published functional studies demonstrate a damaging effect (cells expressing R550X failed to differentiate morphologically and phosphorylation/activation levels of molecules associated with mTOR signaling were decreased) (Sawaguchi et al., 2022); 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: 22855961, 18851904, 22036171, 27535533, 35225888) (less)
|
|
|
Pathogenic
(Mar 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003836119.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
|
Pathogenic
(Nov 11, 2011)
|
no assertion criteria provided
Method: literature only
|
LEUKODYSTROPHY, HYPOMYELINATING, 8, WITHOUT HYPODONTIA OR HYPOGONADOTROPIC HYPOGONADISM
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000045449.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 12, 2015 |
Comment on evidence:
In a 16-year-old Japanese girl with hypomyelinating leukodystrophy-8 (HLD8; 614381), previously reported as patient 1 by Sasaki et al. (2009), Saitsu et al. (2011) identified … (more)
In a 16-year-old Japanese girl with hypomyelinating leukodystrophy-8 (HLD8; 614381), previously reported as patient 1 by Sasaki et al. (2009), Saitsu et al. (2011) identified compound heterozygosity for 2 mutations in the POLR3B gene: a paternally inherited 1648C-T transition in exon 16, resulting in an arg550-to-ter (R550X) substitution, and a maternally inherited 2778C-G transversion in exon 24, resulting in an asp926-to-glu (D926E; 614366.0004) substitution in a highly conserved residue. The R550X transcript was shown to undergo nonsense-mediated mRNA decay. Modeling with the yeast homolog of the pol II subunit suggested that asp926 interacts with the main-chain carbonyl groups in other subunits, and that the D926E substitution would disturb these interactions and cause polymerase dysfunction. Neither mutation was found in 540 Japanese control chromosomes. The patient began to walk unsteadily at age 11 months but retained her ability to walk as a teen. She had cerebellar signs, mild spasticity, slowing of smooth-pursuit eye movements, vertical gaze limitations, and intellectual disability. She did not have hypogonadism or hypodontia. (less)
|
|
|
Pathogenic
(Apr 01, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism
Affected status: yes
Allele origin:
unknown
|
Undiagnosed Diseases Network, NIH
Accession: SCV003915639.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Abnormality of the dentition (present) , Amblyopia (present) , Cerebellar ataxia (present) , Cerebellar atrophy (present) , Dysmetria (present) , Slurred speech (present) , Joint … (more)
Abnormality of the dentition (present) , Amblyopia (present) , Cerebellar ataxia (present) , Cerebellar atrophy (present) , Dysmetria (present) , Slurred speech (present) , Joint laxity (present) , Dysdiadochokinesis (present) , Short stature (present) , Low-frequency sensorineural hearing impairment (present) , High myopia (present) , Midface retrusion (present) (less)
Age: 0-9 years
Sex: female
Tissue: Blood
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000055917.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect (cells expressing R550X failed to differentiate morphologically and phosphorylation/activation levels of molecules associated with mTOR signaling were decreased) (Sawaguchi et al., 2022); 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: 22855961, 18851904, 22036171, 27535533, 35225888)
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:
The p.Arg550Ter variant in POLR3B has been reported in 1 individual in the compound heterozygous state with 4H leukodystrophy (PMID: 22036171), and has been identified in 0.003% (1/34550) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267608688). 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#: 31162) and has been interpreted as pathogenic by GeneReviews and OMIM. In vitro functional studies provide some evidence that the p.Arg550Ter variant may impact protein function (PMID: 22036171). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 550, which is predicted to lead to a truncated or absent protein. Loss of function of the POLR3B gene is an established disease mechanism in autosomal recessive 4H leukodystrophy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive4H leukodystrophy. ACMG/AMP Criteria applied: PVS1, PS3_moderate, PM2_supporting (Richards 2015).
Comment:
Published functional studies demonstrate a damaging effect (cells expressing R550X failed to differentiate morphologically and phosphorylation/activation levels of molecules associated with mTOR signaling were decreased) (Sawaguchi et al., 2022); 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: 22855961, 18851904, 22036171, 27535533, 35225888)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| POLR3-Related Leukodystrophy. | Adam MP | - | 2017 | PMID: 22855961 |
| Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. | Saitsu H | American journal of human genetics | 2011 | PMID: 22036171 |
| Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum. | Sasaki M | Brain & development | 2009 | PMID: 18851904 |
Text-mined citations for rs267608688 ...
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 Mar 30, 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.