ClinVar Genomic variation as it relates to human health
NM_174878.3(CLRN1):c.189C>A (p.Tyr63Ter)
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.189C>A (p.Tyr63Ter)
Variation ID: 4397 Accession: VCV000004397.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q25.1 3: 150972520 (GRCh38) [ NCBI UCSC ] 3: 150690307 (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 28, 2015 Feb 14, 2024 Dec 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_174878.3:c.189C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_777367.1:p.Tyr63Ter nonsense NM_001195794.1:c.189C>A NP_001182723.1:p.Tyr63Ter nonsense NM_001256819.2:c.189C>A NP_001243748.1:p.Tyr63Ter nonsense NR_046380.3:n.208C>A non-coding transcript variant NC_000003.12:g.150972520G>T NC_000003.11:g.150690307G>T NG_009168.1:g.5480C>A LRG_700:g.5480C>A LRG_700t1:c.189C>A LRG_700p1:p.Tyr63Ter - Protein change
- Y63*
- Other names
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- Canonical SPDI
- NC_000003.12:150972519:G: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Sep 7, 2018 | RCV000004647.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 24, 2012 | RCV000844690.4 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2015 | RCV000505037.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2022 | RCV001376502.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 7, 2023 | RCV001384937.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 25, 2023 | RCV003466814.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 21, 2023 | RCV003407275.4 |
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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Pathogenic
(Dec 24, 2012)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065128.5
First in ClinVar: May 03, 2013 Last updated: Oct 11, 2015 |
Comment:
The Tyr63X variant in CLRN1 has been reported in a homozygous state in three sib lings with Usher syndrome from one family (Adato 2002, Aller … (more)
The Tyr63X variant in CLRN1 has been reported in a homozygous state in three sib lings with Usher syndrome from one family (Adato 2002, Aller 2004). This nonsens e variant leads to a premature termination codon at position 63, which is predic ted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). (less)
Number of individuals with the variant: 2
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Pathogenic
(Jun 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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CLRN1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004114993.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The CLRN1 c.189C>A variant is predicted to result in premature protein termination (p.Tyr63*). This variant has been reported to be causative for autosomal recessive Usher … (more)
The CLRN1 c.189C>A variant is predicted to result in premature protein termination (p.Tyr63*). This variant has been reported to be causative for autosomal recessive Usher syndrome or retinitis pigmentosa (Adato et al. 2002. PubMed ID: 12080385; Melo et al. 2014. PubMed ID: 24596593; Carss et al. 2016. PubMed ID: 28041643). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-150690307-G-T). Nonsense variants in CLRN1 are expected to be pathogenic. Given the evidence, we interpret c.189C>A (p.Tyr63*) as pathogenic. (less)
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Pathogenic
(Sep 25, 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: SCV004214406.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 07, 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: SCV001584632.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr63*) in the CLRN1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr63*) in the CLRN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLRN1 are known to be pathogenic (PMID: 11524702, 24498627). This variant is present in population databases (rs111033267, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 12080385, 23304067). ClinVar contains an entry for this variant (Variation ID: 4397). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome, type 3A
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919233.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: CLRN1 c.189C>A (p.Tyr63X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: CLRN1 c.189C>A (p.Tyr63X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.8e-05 in 277198 control chromosomes. c.189C>A has been reported in the literature as a homozygous and compound heterozygous allele in multiple individuals affected with Usher Syndrome Type 3 (Adato_2002; Garcia-Garcia_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 08, 2021)
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criteria provided, single submitter
Method: research
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Usher syndrome type 3A
Affected status: yes
Allele origin:
germline
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Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573675.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The CLRN1 c.189C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The CLRN1 c.189C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1. Based on this evidence we have classified this variant as Pathogenic. (less)
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 3A
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058400.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004397, PMID:12080385). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000014, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present) , Constriction of peripheral visual field (present) , Nyctalopia (present) , Abnormal optic nerve morphology (present) , Retinal vasculitis (present)
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Pathogenic
(Apr 12, 2016)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 3A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000486175.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Dec 01, 2004)
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no assertion criteria provided
Method: literature only
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USHER SYNDROME, TYPE IIIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024821.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 28, 2015 |
Comment on evidence:
In 3 sibs with Usher syndrome type IIIA (USH3A; 276902) from a nonconsanguineous Spanish family, Adato et al. (2002) detected a 189C-A substitution in the … (more)
In 3 sibs with Usher syndrome type IIIA (USH3A; 276902) from a nonconsanguineous Spanish family, Adato et al. (2002) detected a 189C-A substitution in the CLRN1 gene, which was expected to cause a tyr63-to-ter (Y63X) homozygous nonsense mutation. Aller et al. (2004) stated that the family with the Y63X mutation reported by Adato et al. (2002) could be diagnosed clinically with Usher syndrome type I because hearing impairment was profound and stable. Aller et al. (2004) considered that progressive hearing loss is not the definitive parameter in distinguishing Usher syndrome type III from Usher syndrome types I and II. (less)
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Pathogenic
(Jan 01, 2015)
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no assertion criteria provided
Method: research
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Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000598874.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: NA
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Pathogenic
(Sep 11, 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: SCV002081535.1
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 Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. | Carss KJ | American journal of human genetics | 2017 | PMID: 28041643 |
Strategies for genetic study of hearing loss in the Brazilian northeastern region. | Melo US | International journal of molecular epidemiology and genetics | 2014 | PMID: 24596593 |
Experience of targeted Usher exome sequencing as a clinical test. | Besnard T | Molecular genetics & genomic medicine | 2014 | PMID: 24498627 |
Two novel disease-causing mutations in the CLRN1 gene in patients with Usher syndrome type 3. | García-García G | Molecular vision | 2012 | PMID: 23304067 |
Mutation screening of USH3 gene (clarin-1) in Spanish patients with Usher syndrome: low prevalence and phenotypic variability. | Aller E | Clinical genetics | 2004 | PMID: 15521980 |
USH3A transcripts encode clarin-1, a four-transmembrane-domain protein with a possible role in sensory synapses. | Adato A | European journal of human genetics : EJHG | 2002 | PMID: 12080385 |
Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3. | Joensuu T | American journal of human genetics | 2001 | PMID: 11524702 |
Text-mined citations for rs111033267 ...
HelpRecord last updated Mar 11, 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.