ClinVar Genomic variation as it relates to human health
NM_206933.4(USH2A):c.1000C>T (p.Arg334Trp)
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_206933.4(USH2A):c.1000C>T (p.Arg334Trp)
Variation ID: 228411 Accession: VCV000228411.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q41 1: 216325448 (GRCh38) [ NCBI UCSC ] 1: 216498790 (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 May 29, 2016 Feb 14, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206933.4:c.1000C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996816.3:p.Arg334Trp missense NM_007123.6:c.1000C>T NP_009054.6:p.Arg334Trp missense NC_000001.11:g.216325448G>A NC_000001.10:g.216498790G>A NG_009497.2:g.103001C>T O75445:p.Arg334Trp - Protein change
- R334W
- Other names
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- Canonical SPDI
- NC_000001.11:216325447: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
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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USH2A | - | - |
GRCh38 GRCh37 |
6918 | 8386 |
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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Pathogenic (1) |
criteria provided, single submitter
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Apr 27, 2015 | RCV000213203.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 30, 2017 | RCV000668930.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000822071.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 8, 2019 | RCV001074876.1 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 23, 2019 | RCV001003287.1 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Nov 4, 2023 | RCV001273812.2 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 4, 2023 | RCV003454598.2 |
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
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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Likely pathogenic
(Aug 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 2A
Retinitis pigmentosa 39
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000793608.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Apr 27, 2015)
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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: SCV000271469.3
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
The p.Arg334Trp variant in USH2A has been reported in 9 probands with Usher synd rome who were either compound heterozygous or homozygous, and segregated in … (more)
The p.Arg334Trp variant in USH2A has been reported in 9 probands with Usher synd rome who were either compound heterozygous or homozygous, and segregated in 9 fa mily members (Adato 2000, Auslender 2008, Baux 2014, Baux 2007, Dreyer 2000, Jai jo 2009, Krawitz 2014, Ouyang 2004). This variant has been identified in 4/11496 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs397517963), however this frequency is low enough to be co nsistent with a recessive carrier frequency. In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive Usher syndrome b ased on multiple reports with pathogenic USH2A variants in individuals with Ushe r syndrome (http://personalizedmedicine.partners.org/). (less)
Number of individuals with the variant: 2
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Pathogenic
(Aug 08, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001240480.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
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Pathogenic
(May 08, 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: SCV001982941.4
First in ClinVar: Oct 30, 2021 Last updated: May 20, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33124170, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33124170, 32675063, 34781295, 17405132, 10738000, 10909849, 19683999, 25333064, 15025721, 24944099, 26338283, 27032803, 29490346, 31589614, 31456290, 32050993, 18452394, 32531858) (less)
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Likely pathogenic
(Nov 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 39
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004182918.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely pathogenic
(Nov 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 2A
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004182919.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Oct 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 39
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004208187.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 25, 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: SCV000962856.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 334 of the USH2A protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 334 of the USH2A protein (p.Arg334Trp). This variant is present in population databases (rs397517963, gnomAD 0.03%). This missense change has been observed in individuals with Usher syndrome (PMID: 10909849, 15025721, 17405132, 18452394, 19683999, 20513143, 25333064, 26338283, 27032803, 28894305, 28944237, 29142287). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228411). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. This variant disrupts the p.Arg334 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 17405132), which suggests that this may be a clinically significant amino acid residue. 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 2
Affected status: yes
Allele origin:
inherited
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Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001161370.1
First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Usher syndrome type 2A
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001457325.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Targeted next generation sequencing in Italian patients with Usher syndrome: phenotype-genotype correlations. | Eandi CM | Scientific reports | 2017 | PMID: 29142287 |
Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and PEX26 mutated in Heimler syndrome. | Neuhaus C | Molecular genetics & genomic medicine | 2017 | PMID: 28944237 |
Electroretinography Reveals Difference in Cone Function between Syndromic and Nonsyndromic USH2A Patients. | Sengillo JD | Scientific reports | 2017 | PMID: 28894305 |
Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel. | Bravo-Gil N | Scientific reports | 2016 | PMID: 27032803 |
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 |
Screening for single nucleotide variants, small indels and exon deletions with a next-generation sequencing based gene panel approach for Usher syndrome. | Krawitz PM | Molecular genetics & genomic medicine | 2014 | PMID: 25333064 |
Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots. | Baux D | Human mutation | 2014 | PMID: 24944099 |
Nasal epithelial cells are a reliable source to study splicing variants in Usher syndrome. | Vaché C | Human mutation | 2010 | PMID: 20513143 |
Microarray-based mutation analysis of 183 Spanish families with Usher syndrome. | Jaijo T | Investigative ophthalmology & visual science | 2010 | PMID: 19683999 |
Four USH2A founder mutations underlie the majority of Usher syndrome type 2 cases among non-Ashkenazi Jews. | Auslender N | Genetic testing | 2008 | PMID: 18452394 |
Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II. | Dreyer B | Human mutation | 2008 | PMID: 18273898 |
Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients. | Baux D | Human mutation | 2007 | PMID: 17405132 |
Mutational spectrum in Usher syndrome type II. | Ouyang XM | Clinical genetics | 2004 | PMID: 15025721 |
Identification of novel USH2A mutations: implications for the structure of USH2A protein. | Dreyer B | European journal of human genetics : EJHG | 2000 | PMID: 10909849 |
Three novel mutations and twelve polymorphisms identified in the USH2A gene in Israeli USH2 families. | Adato A | Human mutation | 2000 | PMID: 10738000 |
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Text-mined citations for rs397517963 ...
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.