ClinVar Genomic variation as it relates to human health
NM_174878.3(CLRN1):c.433+1G>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_174878.3(CLRN1):c.433+1G>A
Variation ID: 638640 Accession: VCV000638640.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q25.1 3: 150941581 (GRCh38) [ NCBI UCSC ] 3: 150659368 (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 Aug 8, 2019 Feb 20, 2024 Nov 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_174878.3:c.433+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001195794.1:c.433+1G>A splice donor NM_001256819.2:c.*47+1G>A splice donor NM_052995.2:c.205+1G>A splice donor NC_000003.12:g.150941581C>T NC_000003.11:g.150659368C>T NG_009168.1:g.36419G>A LRG_700:g.36419G>A LRG_700t1:c.433+1G>A LRG_700t2:c.205+1G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000003.12:150941580: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00001
- Links
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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CLRN1 | - | - |
GRCh38 GRCh37 |
360 | 408 |
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
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
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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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Mar 15, 2019 | RCV000791320.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 8, 2023 | RCV001387204.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 24, 2023 | RCV003467324.1 |
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
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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
(Mar 15, 2019)
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criteria provided, single submitter
Method: research
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Usher syndrome type 3A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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The Cell Therapy Center, The University of Jordan
Accession: SCV000920580.1
First in ClinVar: Aug 08, 2019 Last updated: Aug 08, 2019 |
Comment:
The c.433+1G>A variant in CLRN1 was found in a Jordanian family with inherited retinal dystrophy. This family was diagnosed with RP until after the molecular … (more)
The c.433+1G>A variant in CLRN1 was found in a Jordanian family with inherited retinal dystrophy. This family was diagnosed with RP until after the molecular assessment showed CLRN1 as the causative gene. Audiometry revealed that all patients have some degree of sensorineural hearing loss which led to the diagnosis of Usher Syndrome. The variant was found in the proband and segregates with the disease. Simulation analysis including molecular and dynamic simulation was done on this variant and showed that it affected splicing tremendously resulting in an abnormal protein. In summary, the variant meets the criteria to be pathogenic based on its segregation, allele frequency, and simulation results. (less)
Number of individuals with the variant: 4
Sex: mixed
Ethnicity/Population group: Arab
Geographic origin: Jordan
Method: Genomic DNA was isolated from peripheral blood samples of the patients and participating family members using QIAprep Spin Miniprep Kit. ES was performed on the proband patients of each family (Figure 1) by Partners HealthCare Personalized Medicine (PPM), Harvard, USA. Briefly, extracted DNA was sheared to 150–200 bp fragments. Exome enrichment was performed using Agilent SureSelect Human All Exon V5 kit (Santa Clara, Californian, U.S.A.). DNA was sequenced using 100 bp paired-end reads on Hiseq 2500 platform (Illumina Inc., San Diego, CA). Raw data were processed by Illumina base-calling software 1.7 using default parameters. The sequencing reads were aligned to the NCBI reference sequence (GRCh37), using the Burrows-Wheeler Aligner (BWA), and variant calls were made using the Genomic Analysis Tool Kit (GATK). The detected variants were annotated and filtered against four databases (i.e., NCBI CCDS (http://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi), RefSeq (http://www.ncbi.nlm.nih.-gov/) RefSeq/), Ensembl (http://www.ensembl.org), and Encode (http://genome.ucsc.edu/ENCODE)).
Testing laboratory: 21766
Testing laboratory interpretation: Pathogenic
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Pathogenic
(Sep 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 61
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004214407.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Nov 08, 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: SCV001587768.5
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects a donor splice site in intron 2 of the CLRN1 gene. While this variant is not anticipated to result in nonsense … (more)
This sequence change affects a donor splice site in intron 2 of the CLRN1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs201205811, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CLRN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 638640). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the CLRN1 protein in which other variant(s) (p.Arg207*) have been determined to be pathogenic (PMID: 22952768, 23304067, 26338283). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 23, 2019)
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no assertion criteria provided
Method: research
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Usher syndrome type 3
Affected status: yes
Allele origin:
inherited
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Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001160989.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
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Pathogenic
(Sep 23, 2020)
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no assertion criteria provided
Method: clinical testing
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Usher syndrome type 3
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002081531.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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Comprehensive molecular diagnosis of 67 Chinese Usher syndrome probands: high rate of ethnicity specific mutations in Chinese USH patients. | Jiang L | Orphanet journal of rare diseases | 2015 | PMID: 26338283 |
Two novel disease-causing mutations in the CLRN1 gene in patients with Usher syndrome type 3. | García-García G | Molecular vision | 2012 | PMID: 23304067 |
Molecular diagnosis of Usher syndrome: application of two different next generation sequencing-based procedures. | Licastro D | PloS one | 2012 | PMID: 22952768 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs201205811 ...
HelpRecord last updated Feb 28, 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.