ClinVar Genomic variation as it relates to human health
NM_206933.4(USH2A):c.2167+5G>A
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.2167+5G>A
Variation ID: 552447 Accession: VCV000552447.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q41 1: 216250898 (GRCh38) [ NCBI UCSC ] 1: 216424240 (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 Aug 5, 2018 Feb 14, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206933.4:c.2167+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_007123.6:c.2167+5G>A intron variant NC_000001.11:g.216250898C>T NC_000001.10:g.216424240C>T NG_009497.2:g.177551G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000001.11:216250897:C: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD) 0.00009
- Links
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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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
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 12, 2021 | RCV000667707.4 | |
Likely pathogenic (1) |
no assertion criteria provided
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Jun 23, 2019 | RCV001003280.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV001035076.7 | |
Pathogenic (1) |
criteria provided, single submitter
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May 22, 2019 | RCV001073540.1 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2023 | RCV001376264.3 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Apr 11, 2023 | RCV001829844.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 20, 2022 | RCV002509496.1 |
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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Likely pathogenic
(Jun 09, 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: SCV000792201.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(May 22, 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: SCV001239087.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
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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: SCV001573343.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The USH2A c.2167+5G>A 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.2167+5G>A 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: PVS1, PM2, PM3. Based on this evidence we have classified this variant as Pathogenic. (less)
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Pathogenic
(Aug 12, 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: SCV000893290.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 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: SCV001982672.2
First in ClinVar: Oct 30, 2021 Last updated: Jan 15, 2023 |
Comment:
Published functional studies demonstrate that c.2167+5G>A causes skipping of exon 12 yielding truncated protein p.Ile658GlyfsX33, and also creates a new 5 donor site resulting in-frame … (more)
Published functional studies demonstrate that c.2167+5G>A causes skipping of exon 12 yielding truncated protein p.Ile658GlyfsX33, and also creates a new 5 donor site resulting in-frame deletion of the 30 last nucleotides of exon 12 (Jaijo et al., 2011); This variant is associated with the following publications: (PMID: 20497194, 25525159, 12112664, 25366773, 30190494, 24944099, 24516651, 21151602, 23647439, 31589614, 33576794, 31456290, 34781295, 32188678) (less)
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Pathogenic
(Dec 20, 2022)
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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: SCV002819702.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: USH2A c.2167+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: USH2A c.2167+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site and one predicts an extreme weakening of this site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in both out-of frame skipping of exon 12 and an in-frame skipping of the exon with the use of an alternate splice site (Jaijo_2011). The variant allele was found at a frequency of 4e-05 in 250350 control chromosomes. This frequency is not higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (4e-05 vs 0.011), allowing no conclusion about variant significance. c.2167+5G>A has been reported in the literature in multiple individuals affected with Usher Syndrome or Retinitis Pigmentosa (Avila-Fernandez_2010, Gao_2021, Jaijo_2011, Najera_2002, Columbo_2021), and some of these patients were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 , and all laboratories classified 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 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: SCV004172185.1
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: SCV004172186.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Pathogenic
(Aug 01, 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: SCV004208362.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 11, 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: SCV001198388.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 12 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 12 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs771583281, gnomAD 0.01%). This variant has been observed in individuals with Usher syndrome 2 or retinitis pigmentosa (PMID: 12112664, 21151602, 24516651, 30190494). This variant is also known as IVS12+5G>A. ClinVar contains an entry for this variant (Variation ID: 552447). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20497194). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jun 23, 2019)
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no assertion criteria provided
Method: research
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Retinitis pigmentosa
Affected status: yes
Allele origin:
inherited
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Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001161363.1
First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020 |
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Pathogenic
(Dec 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: SCV002093962.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 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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Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome. | Colombo L | Investigative ophthalmology & visual science | 2021 | PMID: 33576794 |
Prevalence and genetic-phenotypic characteristics of patients with USH2A mutations in a large cohort of Chinese patients with inherited retinal disease. | Gao FJ | The British journal of ophthalmology | 2021 | PMID: 32188678 |
Searching the second hit in patients with inherited retinal dystrophies and monoallelic variants in ABCA4, USH2A and CEP290 by whole-gene targeted sequencing. | González-Del Pozo M | Scientific reports | 2018 | PMID: 30190494 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Syndromic and non-syndromic forms of retinitis pigmentosa: a comprehensive Italian clinical and molecular study reveals new mutations. | Pierrottet CO | Genetics and molecular research : GMR | 2014 | PMID: 25366773 |
Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots. | Baux D | Human mutation | 2014 | PMID: 24944099 |
Combined genetic and high-throughput strategies for molecular diagnosis of inherited retinal dystrophies. | de Castro-Miró M | PloS one | 2014 | PMID: 24516651 |
Functional analysis of splicing mutations in MYO7A and USH2A genes. | Jaijo T | Clinical genetics | 2011 | PMID: 20497194 |
Mutation analysis of 272 Spanish families affected by autosomal recessive retinitis pigmentosa using a genotyping microarray. | Ávila-Fernández A | Molecular vision | 2010 | PMID: 21151602 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Mutations in myosin VIIA (MYO7A) and usherin (USH2A) in Spanish patients with Usher syndrome types I and II, respectively. | Nájera C | Human mutation | 2002 | PMID: 12112664 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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Text-mined citations for rs771583281 ...
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.