ClinVar Genomic variation as it relates to human health
NM_203290.4(POLR1C):c.326G>A (p.Arg109His)
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_203290.4(POLR1C):c.326G>A (p.Arg109His)
Variation ID: 204592 Accession: VCV000204592.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.1 6: 43519782 (GRCh38) [ NCBI UCSC ] 6: 43487520 (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 Oct 9, 2016 Nov 4, 2023 Sep 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_203290.4:c.326G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_976035.1:p.Arg109His missense NM_001318876.2:c.326G>A NP_001305805.1:p.Arg109His missense NM_001363658.2:c.326G>A NP_001350587.1:p.Arg109His missense NC_000006.12:g.43519782G>A NC_000006.11:g.43487520G>A NG_028283.3:g.15081G>A O15160:p.Arg109His - Protein change
- R109H
- Other names
- -
- Canonical SPDI
- NC_000006.12:43519781: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD) 0.00002
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
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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
Help
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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POLR1C | - | - |
GRCh38 GRCh37 |
183 | 2420 |
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
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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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- | RCV000186589.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 3, 2016 | RCV000853238.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 27, 2023 | RCV003387792.1 |
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
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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
(-)
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criteria provided, single submitter
Method: research
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Leukodystrophy, hypomyelinating, 11
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
maternal
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MyeliNeuroGene Lab, McGill University Health Center Research Institute
Accession: SCV000924596.1
First in ClinVar: Jul 22, 2019 Last updated: Jul 22, 2019 |
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Likely pathogenic
(Nov 03, 2016)
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criteria provided, single submitter
Method: clinical testing
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TREACHER COLLINS SYNDROME 3
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996051.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
The c.326G>A (p.Arg109His) variant is a missense variant in the POLR1C gene. This missense variant is absent from the 1000 Genomes, Exome Variant Server (EVS), … (more)
The c.326G>A (p.Arg109His) variant is a missense variant in the POLR1C gene. This missense variant is absent from the 1000 Genomes, Exome Variant Server (EVS), and Exome Aggregation Corsotium (ExAC) databases. Thus, it is presumed to be rare. The p.Arg109His variant was reported in the compound heterozygous state in two patients with leukodystrophy (PMID: 26151409). The amino acid position is highly conserved and in silico algorithms predict the variant to be damaging. Based on the combined information, the p.Arg109His variant is classified as a likely pathogenic variant. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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POLR1C-Related Disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004100231.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Variant summary: POLR1C c.326G>A (p.Arg109His) results in a non-conservative amino acid change located in the DNA-directed RNA polymerase, insert domain (IPR011262) of the encoded protein … (more)
Variant summary: POLR1C c.326G>A (p.Arg109His) results in a non-conservative amino acid change located in the DNA-directed RNA polymerase, insert domain (IPR011262) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251486 control chromosomes (gnomAD). c.326G>A has been reported in the literature in compound heterozygous individuals affected with Leukodystrophy (Thiffault_2015, Farnaes_2018, Clark_2019, Yan_2021, De La Vega_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33804237, 31019026, 34645491, 29644095, 33888711, 26151409, 33597727). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Jul 07, 2015)
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no assertion criteria provided
Method: literature only
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LEUKODYSTROPHY, HYPOMYELINATING, 11
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000240165.2
First in ClinVar: Aug 01, 2015 Last updated: Oct 09, 2016 |
Comment on evidence:
For discussion of the c.326G-A transition (c.326G-A, NM_203290) in the POLR1C gene, resulting in an arg109-to-his (R109H) substitution, that was found in compound heterozygous state … (more)
For discussion of the c.326G-A transition (c.326G-A, NM_203290) in the POLR1C gene, resulting in an arg109-to-his (R109H) substitution, that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-11 (HLD11; 616494) by Thiffault et al. (2015), see 610060.0010. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Hypomyelinating leukodystrophy 11
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV001760711.2
First in ClinVar: Jul 24, 2021 Last updated: Oct 01, 2022 |
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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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Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases. | De La Vega FM | Genome medicine | 2021 | PMID: 34645491 |
Rapid whole genome sequencing impacts care and resource utilization in infants with congenital heart disease. | Sweeney NM | NPJ genomic medicine | 2021 | PMID: 33888711 |
Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia. | Ching-López A | International journal of molecular sciences | 2021 | PMID: 33804237 |
Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing. | Yan H | Journal of human genetics | 2021 | PMID: 33597727 |
Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation. | Clark MM | Science translational medicine | 2019 | PMID: 31019026 |
Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. | Farnaes L | NPJ genomic medicine | 2018 | PMID: 29644095 |
Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III. | Thiffault I | Nature communications | 2015 | PMID: 26151409 |
Epididymal sarcoidosis: a report of two cases and a review of the literature. | Gerstenhaber BJ | The Yale journal of biology and medicine | 1977 | PMID: 610060 |
Text-mined citations for rs796052127 ...
HelpRecord last updated Nov 04, 2023
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.