ClinVar Genomic variation as it relates to human health
NM_174878.3(CLRN1):c.368C>A (p.Ala123Asp)
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.368C>A (p.Ala123Asp)
Variation ID: 48146 Accession: VCV000048146.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q25.1 3: 150941647 (GRCh38) [ NCBI UCSC ] 3: 150659434 (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 Mar 29, 2015 Feb 14, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_174878.3:c.368C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_777367.1:p.Ala123Asp missense NM_001195794.1:c.368C>A NP_001182723.1:p.Ala123Asp missense NM_001256819.2:c.540C>A NP_001243748.1:p.Cys180Ter nonsense NM_052995.2:c.140C>A NP_443721.1:p.Ala47Asp missense NR_046380.3:n.538C>A non-coding transcript variant NC_000003.12:g.150941647G>T NC_000003.11:g.150659434G>T NG_009168.1:g.36353C>A LRG_700:g.36353C>A LRG_700t1:c.368C>A LRG_700p1:p.Ala123Asp LRG_700t2:c.140C>A LRG_700p2:p.Ala47Asp - Protein change
- A123D, A47D, C180*
- Other names
- -
- Canonical SPDI
- NC_000003.12:150941646: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00012
The Genome Aggregation Database (gnomAD) 0.00018
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
1000 Genomes Project 30x 0.00031
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
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. |
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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
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. |
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Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 27, 2014 | RCV000041436.9 | |
Pathogenic (1) |
criteria provided, single submitter
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May 17, 2011 | RCV000844624.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001071445.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 24, 2021 | RCV001582535.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2022 | RCV002243688.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 19, 2023 | RCV003466890.1 |
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
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
(May 17, 2011)
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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: SCV000065131.5
First in ClinVar: May 03, 2013 Last updated: May 27, 2015 |
Comment:
The Ala123Asp variant has been reported in two individuals with Usher syndrome a nd was absent from 566 control chromosomes (Ebermann 2007, Isosomppi 2009). In … (more)
The Ala123Asp variant has been reported in two individuals with Usher syndrome a nd was absent from 566 control chromosomes (Ebermann 2007, Isosomppi 2009). In a ddition, functional studies showed that the variant protein is not correctly loc alized in the cell and is rapidly degraded (Isosomppi 2009). In summary, this da ta meets our criteria to classify this variant as pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(-)
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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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Baylor Genetics
Accession: SCV001162963.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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Likely pathogenic
(Jun 27, 2014)
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criteria provided, single submitter
Method: literature only
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Usher syndrome, type 3
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220455.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Oct 19, 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: SCV004214402.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 31, 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: SCV001236751.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 123 of the CLRN1 protein … (more)
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 123 of the CLRN1 protein (p.Ala123Asp). This variant is present in population databases (rs374963432, gnomAD 0.04%). This missense change has been observed in individuals with Usher syndrome (PMID: 7407589, 19753315, 27460420). ClinVar contains an entry for this variant (Variation ID: 48146). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLRN1 function (PMID: 19753315). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001821386.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Variant summary: CLRN1 c.368C>A (p.Ala123Asp) results in a non-conservative amino acid change located in the transmembrane domain (Yoshimura_2015) of the encoded protein sequence. Five of … (more)
Variant summary: CLRN1 c.368C>A (p.Ala123Asp) results in a non-conservative amino acid change located in the transmembrane domain (Yoshimura_2015) 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 3.9e-05 in 283350 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in CLRN1 causing Usher Syndrome (3.9e-05 vs 0.0014), allowing no conclusion about variant significance. c.368C>A has been reported in the literature in multiple individuals affected with Usher Syndrome, including two homozygotes (Ebermann_2007, Isosomppi_2009, Bonnet_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in CLRN1 protein retained in the ER and not trafficked to the plasma membrane (Isosomppi_2009). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jan 04, 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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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512705.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 moderate, PM2 moderate, PM3 supporting, PP3 supporting
Geographic origin: Brazil
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Pathogenic
(Jan 13, 2021)
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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: SCV002081534.1
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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Unconventional secretory pathway activation restores hair cell mechanotransduction in an USH3A model. | Gopal SR | Proceedings of the National Academy of Sciences of the United States of America | 2019 | PMID: 31097578 |
An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients. | Bonnet C | European journal of human genetics : EJHG | 2016 | PMID: 27460420 |
Identification of a novel CLRN1 gene mutation in Usher syndrome type 3: two case reports. | Yoshimura H | The Annals of otology, rhinology, and laryngology | 2015 | PMID: 25743179 |
Two novel disease-causing mutations in the CLRN1 gene in patients with Usher syndrome type 3. | García-García G | Molecular vision | 2012 | PMID: 23304067 |
Disease-causing mutations in the CLRN1 gene alter normal CLRN1 protein trafficking to the plasma membrane. | Isosomppi J | Molecular vision | 2009 | PMID: 19753315 |
Deafblindness in French Canadians from Quebec: a predominant founder mutation in the USH1C gene provides the first genetic link with the Acadian population. | Ebermann I | Genome biology | 2007 | PMID: 17407589 |
Sodium-dependent interaction of benzamides with dopamine receptors. | Stefanini E | Brain research | 1980 | PMID: 7407589 |
Text-mined citations for rs374963432 ...
HelpRecord last updated Feb 20, 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.