ClinVar Genomic variation as it relates to human health
NM_206933.4(USH2A):c.9424G>T (p.Gly3142Ter)
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.9424G>T (p.Gly3142Ter)
Variation ID: 48626 Accession: VCV000048626.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q41 1: 215817143 (GRCh38) [ NCBI UCSC ] 1: 215990485 (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 Feb 24, 2015 Apr 15, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206933.4:c.9424G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996816.3:p.Gly3142Ter nonsense NC_000001.11:g.215817143C>A NC_000001.10:g.215990485C>A NG_009497.2:g.611306G>T - Protein change
- G3142*
- Other names
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- Canonical SPDI
- NC_000001.11:215817142:C: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
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
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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 | 8387 |
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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Jul 20, 2018 | RCV000041952.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 3, 2015 | RCV000624783.3 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 23, 2019 | RCV001003263.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV001055909.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 11, 2019 | RCV001074810.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 1, 2021 | RCV001723630.4 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Nov 4, 2023 | RCV001831709.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 4, 2021 | RCV002504928.2 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 4, 2023 | RCV003387741.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 14, 2023 | RCV003492342.1 |
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
(Jul 11, 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: SCV001240408.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
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Pathogenic
(Oct 04, 2021)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002816438.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 03, 2015)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000740836.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Rod-cone dystrophy (present) , Nyctalopia (present) , Cataract (disease) (present) , Hypertensive disorder (present) , Progressive visual loss (present)
Sex: male
Ethnicity/Population group: Caucasian
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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: SCV004182692.1
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: SCV004182693.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Oct 27, 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: SCV004207713.1
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: SCV001220324.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gly3142*) in the USH2A gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gly3142*) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs397518048, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with Usher syndrome and inherited retinal degeneration (PMID: 17405132, 23591405, 28130426, 28653555). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48626). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246990.20
First in ClinVar: May 09, 2020 Last updated: Apr 15, 2024 |
Comment:
USH2A: PM3:Very Strong, PVS1, PM2, PP4
Number of individuals with the variant: 2
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Pathogenic
(Jul 20, 2018)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
Usher syndrome (Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065648.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
The p.Gly3142X variant has been reported in 9 individuals with Usher syndrome, 4 patients with retinal dystrophy, and 1 patient with sensorineural hearing loss, and … (more)
The p.Gly3142X variant has been reported in 9 individuals with Usher syndrome, 4 patients with retinal dystrophy, and 1 patient with sensorineural hearing loss, and at least 10 of these individuals were compound heterozygous for a second pa thogenic USH2A variant (Baux 2007, Sandberg 2008, McGee 2010, Glockle 2013, Kraw itz 2014, Baux 2014, Lenarduzzi 2015, Lenassi 2015, Bonnet 2016, LMM data). This variant was identified in 0.005% (5/110538) of European chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org); however, thi s frequency is low enough to be consistent with a recessive carrier frequency. T his nonsense variant leads to a premature termination codon at position 3142, wh ich is predicted to lead to a truncated or absent protein. In summary, this vari ant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the predicted impact of the variant, the reported compound het erozygous individuals with Usher syndrome, and its low frequency in the general population. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PM2, PP4. (less)
Number of individuals with the variant: 2
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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: SCV001446933.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Rod-cone dystrophy (present)
Sex: male
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Likely pathogenic
(Apr 01, 2021)
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criteria provided, single submitter
Method: curation
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Retinitis pigmentosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001950406.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
The p.Gly3142Ter variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more)
The p.Gly3142Ter variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
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Pathogenic
(Dec 14, 2023)
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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: SCV004241515.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: USH2A c.9424G>T (p.Gly3142X) results in a premature termination codon and is predicted to cause absence of the protein due to nonsense mediated decay, … (more)
Variant summary: USH2A c.9424G>T (p.Gly3142X) results in a premature termination codon and is predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant allele was found at a frequency of 2.4e-05 in 250190 control chromosomes (gnomAD). c.9424G>T has been reported in the literature as a biallelic genotype in individuals affected with Usher Syndrome (e.g. Neuhaus_2017). These data indicate that the variant is very likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 28944237). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Jul 10, 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: SCV002088403.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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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: SCV001161346.1
First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020 |
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Pathogenic
(Oct 30, 2023)
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no assertion criteria provided
Method: clinical testing
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Retinitis pigmentosa 39
Affected status: yes
Allele origin:
germline
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Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004099464.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
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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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The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK). | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906470 |
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 |
Usher's Syndrome Type II: A Comparative Study of Genetic Mutations and Vestibular System Evaluation. | Magliulo G | Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery | 2017 | PMID: 28653555 |
Genetic analysis of 10 pedigrees with inherited retinal degeneration by exome sequencing and phenotype-genotype association. | Biswas P | Physiological genomics | 2017 | PMID: 28130426 |
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 |
A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants. | Lenassi E | European journal of human genetics : EJHG | 2015 | PMID: 25649381 |
Usher syndrome: an effective sequencing approach to establish a genetic and clinical diagnosis. | Lenarduzzi S | Hearing research | 2015 | PMID: 25575603 |
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 |
Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies. | Glöckle N | European journal of human genetics : EJHG | 2014 | PMID: 23591405 |
Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa. | McGee TL | Journal of medical genetics | 2010 | PMID: 20507924 |
Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene. | Sandberg MA | Investigative ophthalmology & visual science | 2008 | PMID: 18641288 |
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 |
Novel USH2A mutations in Israeli patients with retinitis pigmentosa and Usher syndrome type 2. | Kaiserman N | Archives of ophthalmology (Chicago, Ill. : 1960) | 2007 | PMID: 17296898 |
Identification of novel USH2A mutations: implications for the structure of USH2A protein. | Dreyer B | European journal of human genetics : EJHG | 2000 | PMID: 10909849 |
Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa. | Weston MD | American journal of human genetics | 2000 | PMID: 10729113 |
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Text-mined citations for rs397518048 ...
HelpRecord last updated Apr 15, 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.