ClinVar Genomic variation as it relates to human health
NM_206933.4(USH2A):c.7595-2144A>G
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.7595-2144A>G
Variation ID: 30722 Accession: VCV000030722.48
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q41 1: 215891198 (GRCh38) [ NCBI UCSC ] 1: 216064540 (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 Sep 9, 2017 Mar 10, 2024 Jan 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206933.4:c.7595-2144A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000001.11:g.215891198T>C NC_000001.10:g.216064540T>C NG_009497.2:g.537251A>G - Protein change
- Other names
- IVS40AS, A-G, -2144
- Canonical SPDI
- NC_000001.11:215891197:T: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00007
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 |
6920 | 8391 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000023700.11 | |
Pathogenic (3) |
criteria provided, single submitter
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Oct 30, 2020 | RCV000505092.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000664608.3 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 1, 2018 | RCV000787740.2 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 8, 2024 | RCV000814767.32 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 23, 2019 | RCV001003267.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 18, 2019 | RCV001074209.3 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2023 | RCV001376510.5 | |
Pathogenic (2) |
criteria provided, single submitter
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Nov 7, 2022 | RCV001824575.4 |
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
(Mar 18, 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: SCV001239782.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
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Pathogenic
(Oct 30, 2020)
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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: SCV001442777.1
First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020 |
Comment:
Variant summary: USH2A c.7595-2144A>G is reported in the literature to induce activation of a pseudoexon, predicted to result in a frameshift of the protein (e.g. … (more)
Variant summary: USH2A c.7595-2144A>G is reported in the literature to induce activation of a pseudoexon, predicted to result in a frameshift of the protein (e.g. Vache_2011). Several computational tools predict a significant impact on normal splicing: Four predict that the variant creates a new 5' donor site. The variant allele was found at a frequency of 6.4e-05 in 31406 control chromosomes. c.7595-2144A>G has been reported in the literature in multiple individuals affected with Usher Syndrome, including evidence for cosegregation with disease in several families (e.g. Vache_2011, Steele-Stallard_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant activates a pseudoexon, resulting in aberrant splicing (e.g. Vache_2011). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Apr 08, 2021)
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criteria provided, single submitter
Method: research
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Retinitis pigmentosa 39
Affected status: yes
Allele origin:
germline
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Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573685.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The USH2A c.7595-2144A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The USH2A c.7595-2144A>G 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: PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 2A
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760014.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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Pathogenic
(Nov 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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USH2A-related disorders
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Variantyx, Inc.
Accession: SCV002754525.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
This is a non-canonical splice variant in the USH2A gene (OMIM 608400). Pathogenic variants in this gene have been associated with autosomal recessive USH2A-related disorders. … (more)
This is a non-canonical splice variant in the USH2A gene (OMIM 608400). Pathogenic variants in this gene have been associated with autosomal recessive USH2A-related disorders. This variant causes a splicing defect that results in retention of a 152-bp intronic segment at the junction of exons 40 and 41 (PMID: 22009552). This event introduces a premature stop codon and results in loss of function, which is a known disease mechanism for USH2A (PMID: 20507924) (PVS1). This variant has been observed in the homozygous or compound heterozygous state in several affected individuals, including evidence of segregation with disease in at least two families (PMID: 22009552, 23924366) (PP1_Moderate). This variant has a 0.01928% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/), which is lower than expected for the prevalence of USH2A-related disease (PM2_Supporting). Based on current evidence, this variant is classified as pathogenic for autosomal recessive USH2A-related disorders. (less)
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Pathogenic
(Mar 07, 2022)
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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: SCV001780430.4
First in ClinVar: Aug 11, 2021 Last updated: Mar 04, 2023 |
Comment:
Observed with a second USH2A variant in multiple individuals with Usher syndrome in the published literature, however, the phase of these variants is unknown (Sodi … (more)
Observed with a second USH2A variant in multiple individuals with Usher syndrome in the published literature, however, the phase of these variants is unknown (Sodi et al., 2018; Khalaileh et al., 2018; Steele-Stallard et al., 2013); Non-canonical splice site variant demonstrated to result in loss-of-function; functional studies demonstrated an insertion of 152 bp at the junction of exons 40 and 41, leading to an out-of-frame protein with premature stop codon in exon 41 (designated p.K2532TfsX56) (Vache et al., 2012; Steele-Stallard et al., 2013); This variant is associated with the following publications: (PMID: 25404053, 33576794, 31980526, 31456290, 32581362, 31231422, 30718709, 26629787, 23924366, 30281416, 27802265, 25649381, 25823529, 28041643, 22009552, 25352746, 29490346, 25558175, 27460420, 32037395) (less)
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Pathogenic
(Oct 31, 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: SCV004207691.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(May 14, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002020838.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(May 01, 2019)
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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: SCV001246998.17
First in ClinVar: May 09, 2020 Last updated: Mar 10, 2024 |
Number of individuals with the variant: 5
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Pathogenic
(Apr 28, 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: SCV000788602.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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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: SCV001446946.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Rod-cone dystrophy (present) , Myalgia (present)
Sex: female
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Likely pathogenic
(Apr 11, 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: SCV004172076.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Likely pathogenic
(Apr 11, 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: SCV004172077.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Pathogenic
(Jan 08, 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: SCV000955192.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 40 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. … (more)
This sequence change falls in intron 40 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs786200928, gnomAD 0.007%). This variant has been observed in individual(s) with Usher syndrome (PMID: 22009552, 23924366). 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. ClinVar contains an entry for this variant (Variation ID: 30722). Studies have shown that this variant results in an insertion of 152bp at the junction of exons 40 and 41 and introduces a premature termination codon (PMID: 22009552). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2012)
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no assertion criteria provided
Method: literature only
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USHER SYNDROME, TYPE IIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000044991.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 14, 2018 |
Comment on evidence:
In a French patient with Usher syndrome type IIa (USH2A; 276901), Vache et al. (2012) identified compound heterozygosity for 2 mutations in the USH2A gene: … (more)
In a French patient with Usher syndrome type IIa (USH2A; 276901), Vache et al. (2012) identified compound heterozygosity for 2 mutations in the USH2A gene: a heterozygous A-to-G transition deep within intron 40 (c.7595-2144) and a 1-bp duplication (3129dupT; 608400.0014), resulting in a frameshift. Two other individuals in a different branch of the family had the intron 41 mutation and a different heterozygous frameshift mutation, 8890dupT (608400.0015). The intron 41 mutation was found only after RT-PCR amplification of RNA from nasal cells in 1 patient showed an aberrant USH2A out-of-frame transcript predicted to result in a truncated protein that would not be anchored to the cell membrane. DNA studies showed that the A-to-G transition resulted in activation of a pseudoexon between exons 40 and 41, causing a 153-bp insertion and a frameshift. The nomenclature used for this insertion was r.7594_7595ins7595-2296_7595-2143. This mutation was not found in 338 alleles. However, this mutation was found in 4 of 20 USH2A patients with no identified mutation or only a single pathogenic mutation, as well as in 4 of 18 Spanish patients with incomplete USH2A genotypes. Vache et al. (2012) noted that the identification of a deep intronic mutation in a pseudoexon raised the possibility of a new therapeutic strategy using antisense oligonucleotide chemistry to restore normal splicing via exon skipping. (less)
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Pathogenic
(Apr 01, 2018)
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no assertion criteria provided
Method: research
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Usher syndrome
Affected status: yes
Allele origin:
unknown
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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926743.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
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Pathogenic
(Apr 01, 2018)
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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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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926744.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
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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: SCV001161350.1
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: SCV001458119.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965273.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Likely pathogenic
(Jan 01, 2015)
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no assertion criteria provided
Method: research
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Usher syndrome
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000598828.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001917640.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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USH2A-Related Disorders
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002074877.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant interpreted as Pathogenic and reported on 06-28-2019 by Lab or GTR ID 500188. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 06-28-2019 by Lab or GTR ID 500188. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Premature birth (present) , Abnormal retinal morphology (present) , Hearing impairment (present)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: male
Method: Sanger Sequencing
Testing laboratory: Blueprint Genetics
Date variant was reported to submitter: 2019-06-28
Testing laboratory interpretation: Pathogenic
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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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Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
The Genetics of Usher Syndrome in the Israeli and Palestinian Populations. | Khalaileh A | Investigative ophthalmology & visual science | 2018 | PMID: 29490346 |
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 |
Whole USH2A Gene Sequencing Identifies Several New Deep Intronic Mutations. | Liquori A | Human mutation | 2016 | PMID: 26629787 |
MYO7A and USH2A gene sequence variants in Italian patients with Usher syndrome. | Sodi A | Molecular vision | 2014 | PMID: 25558175 |
Targeted next generation sequencing for molecular diagnosis of Usher syndrome. | Aparisi MJ | Orphanet journal of rare diseases | 2014 | PMID: 25404053 |
Screening for duplications, deletions and a common intronic mutation detects 35% of second mutations in patients with USH2A monoallelic mutations on Sanger sequencing. | Steele-Stallard HB | Orphanet journal of rare diseases | 2013 | PMID: 23924366 |
Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy. | Vaché C | Human mutation | 2012 | PMID: 22009552 |
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 |
Text-mined citations for rs786200928 ...
HelpRecord last updated Mar 17, 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.