ClinVar Genomic variation as it relates to human health
NM_052995.2(CLRN1):c.300T>G (p.Tyr100Ter)
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_052995.2(CLRN1):c.300T>G (p.Tyr100Ter)
Variation ID: 4392 Accession: VCV000004392.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q25.1 3: 150928107 (GRCh38) [ NCBI UCSC ] 3: 150645894 (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 Jun 17, 2024 Mar 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_174878.3:c.528T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_777367.1:p.Tyr176Ter NM_001195794.1:c.567T>G NP_001182723.1:p.Tyr189Ter nonsense NM_001256819.2:c.*142T>G NM_052995.2:c.300T>G NP_443721.1:p.Tyr100Ter NR_046380.3:n.737T>G NC_000003.12:g.150928107A>C NC_000003.11:g.150645894A>C NG_009168.1:g.49893T>G LRG_700:g.49893T>G LRG_700t1:c.567T>G LRG_700p1:p.Tyr189Ter LRG_700t2:c.300T>G LRG_700p2:p.Tyr100Ter - Protein change
- Y176*, Y100*, Y189*
- Other names
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- Canonical SPDI
- NC_000003.12:150928106:A:C
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00049
The Genome Aggregation Database (gnomAD) 0.00089
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 |
366 | 414 |
Conditions - Germline
Condition
Help
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 (6) |
criteria provided, single submitter
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Dec 14, 2018 | RCV000004642.12 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 19, 2024 | RCV000724158.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2022 | RCV002496258.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 26, 2013 | RCV000844623.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2024 | RCV003466811.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 12, 2021 | RCV001375084.4 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2022 | RCV002247246.2 |
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
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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
(Dec 29, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000700728.2
First in ClinVar: May 29, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Dec 14, 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: SCV000919234.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: CLRN1 c.528T>G (p.Tyr176X) 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.528T>G (p.Tyr176X) 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 0.00073 in 277070 control chromosomes in the gnomAD database, including 2 homozygotes. The variant, c.528T>G, has been reported in the literature in multiple individuals affected with Usher Syndrome Type 3 and is considered the most common disease variant in Finland (Joensuu_2001, Isosomppi_2009). 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 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 26, 2013)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000203992.3
First in ClinVar: Jan 31, 2015 Last updated: May 29, 2016 |
Comment:
The Tyr176X variant in CLRN1 has been previously identified in 52 homozygous and 2 compound heterozygous individuals with Usher syndrome type III (Joensuu 2001) . … (more)
The Tyr176X variant in CLRN1 has been previously identified in 52 homozygous and 2 compound heterozygous individuals with Usher syndrome type III (Joensuu 2001) . This variant has been identified in 1/8,600 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1 21908140). Although this variant has been seen in the general population, its fr equency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 176, which i s predicted to lead to a truncated or absent protein. In summary, this variant m eets our criteria to be classified as pathogenic in a recessive manner for Ushe r syndrome (http://pcpgm.partners.org/LMM). (less)
Number of individuals with the variant: 3
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Likely pathogenic
(Apr 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
Affected status: yes
Allele origin:
germline
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Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center
Accession: SCV001571901.2
First in ClinVar: May 01, 2021 Last updated: May 01, 2021 |
Comment:
PVS1_Strong, PM2_Moderate,
Testing laboratory: CeGaT Praxis fuer Humangenetik Tuebingen
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Pathogenic
(Jan 19, 2024)
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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: SCV000935679.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr176*) in the CLRN1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Tyr176*) in the CLRN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the CLRN1 protein. This variant is present in population databases (rs121908140, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Usher syndrome type 3 (PMID: 11524702, 12145752, 22681893). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Y100X. ClinVar contains an entry for this variant (Variation ID: 4392). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CLRN1 function (PMID: 19753315). 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
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447860.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Rod-cone dystrophy (present)
Sex: male
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518724.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Jan 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa
Usher syndrome type 3A Retinitis pigmentosa 61
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002807868.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001813545.2
First in ClinVar: Sep 08, 2021 Last updated: Aug 13, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation, as the last 57 amino acids are lost, and other loss-of-function variants have been reported downstream in … (more)
Nonsense variant predicted to result in protein truncation, as the last 57 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD.; This variant is associated with the following publications: (PMID: 29068140, 27460420, 29490346, 11524702, 25525159, 31456290, 35481838) (less)
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Pathogenic
(Mar 11, 2024)
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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: SCV004214399.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Sep 01, 2002)
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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: SCV000024816.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 28, 2015 |
Comment on evidence:
Fields et al. (2002) demonstrated that the Fin(major) USH3A mutation in exon 3 of the USH3A gene, which had been identified by Joensuu et al. … (more)
Fields et al. (2002) demonstrated that the Fin(major) USH3A mutation in exon 3 of the USH3A gene, which had been identified by Joensuu et al. (2001) as 300C-T (TYR100TER), should be referred to as 528T-G, resulting in a tyr176-to-ter substitution. Joensuu et al. (2001) had identified homozygosity for this mutation in a Finnish family segregating Usher syndrome type IIIA (USH3A; 276902) and found it in a further 52 Finnish patients. Fields et al. (2002) found this mutation in 11 of 28 mutated alleles from affected individuals of Finnish and other northern European ancestry. (less)
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Pathogenic
(Sep 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Usher syndrome type 3A
Affected status: yes
Allele origin:
inherited
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Accession: SCV000804617.2
First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018 |
Number of individuals with the variant: 1
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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: SCV001160987.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
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Pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Usher syndrome, type 3A
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142331.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_174878.2:c.528T>G in the CLRN1 gene has an allele frequency of 0.007 in European (Finnish) subpopulation in the gnomAD database. This nonsense c.528T>G (p.Tyr176*) variant has … (more)
NM_174878.2:c.528T>G in the CLRN1 gene has an allele frequency of 0.007 in European (Finnish) subpopulation in the gnomAD database. This nonsense c.528T>G (p.Tyr176*) variant has been previously identified in 52 homozygous and 2 compound heterozygous individuals with Usher syndrome type III (PMID: 11524702). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP4. (less)
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Pathogenic
(May 30, 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: SCV002081528.1
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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Extended mutation spectrum of Usher syndrome in Finland. | Västinsalo H | Acta ophthalmologica | 2013 | PMID: 22681893 |
Disease-causing mutations in the CLRN1 gene alter normal CLRN1 protein trafficking to the plasma membrane. | Isosomppi J | Molecular vision | 2009 | PMID: 19753315 |
Usher syndrome type III: revised genomic structure of the USH3 gene and identification of novel mutations. | Fields RR | American journal of human genetics | 2002 | PMID: 12145752 |
Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3. | Joensuu T | American journal of human genetics | 2001 | PMID: 11524702 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CLRN1 | - | - | - | - |
Text-mined citations for rs121908140 ...
HelpRecord last updated Jun 23, 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.