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. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201657446, gnomAD 0.002%). This variant has been observed in individual(s) with Usher syndrome type II (PMID: 17405132, 22135276, 24944099, 25097241, 26969326). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197447). 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: 20052763). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_206933.4(USH2A):c.7595-3C>G
Germline
Classification
Help
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.
(13)
Help
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.
Pathogenic/Likely pathogenic
13
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_206933.4(USH2A):c.7595-3C>G
Variation ID: 197447 Accession: VCV000197447.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q41 1: 215889057 (GRCh38) [ NCBI UCSC ] 1: 216062399 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 28, 2015 Oct 8, 2024 Feb 9, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_206933.4:c.7595-3C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000001.11:g.215889057G>C NC_000001.10:g.216062399G>C NG_009497.2:g.539392C>G - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000001.11:215889056:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| USH2A | - | - |
GRCh38 GRCh37 |
7084 | 8579 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 9, 2024 | RCV000178475.14 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jan 1, 2015 | RCV000504696.1 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 8, 2022 | RCV000669197.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 14, 2019 | RCV001075871.2 | |
| Likely pathogenic (3) |
criteria provided, single submitter
|
Apr 11, 2023 | RCV001542728.5 | |
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 20, 2023 | RCV003445607.3 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 20, 2024 | RCV004537466.3 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Usher syndrome type 2A
Retinitis pigmentosa 39
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000793926.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
|
Pathogenic
(Jan 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Usher syndrome type 2A
Retinitis pigmentosa 39
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002793763.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jan 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001202174.5
First in ClinVar: Apr 15, 2020 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. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201657446, gnomAD 0.002%). This variant has been observed in individual(s) with Usher syndrome type II (PMID: 17405132, 22135276, 24944099, 25097241, 26969326). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197447). 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: 20052763). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Dec 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 39
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004208162.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Feb 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001811549.2
First in ClinVar: Sep 08, 2021 Last updated: Sep 16, 2024 |
Comment:
Results in gain of a new acceptor splice site in intron 40; Published minigene assays demonstrate abnormal gene splicing with insertion of intronic sequence in … (more)
Results in gain of a new acceptor splice site in intron 40; Published minigene assays demonstrate abnormal gene splicing with insertion of intronic sequence in the open reading frame, resulting in a frameshift and premature termination of translation (PMID: 20052763); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25649381, 24944099, 27208204, 34758253, 25097241, 22135276, 27460420, 20052763, 17405132, 26969326, 28981474, 28041643, 32176120, 32581362, 31589614, 36011334, 34948090, 31816670, 35266249, 31964843, 36819107) (less)
|
|
|
Likely pathogenic
(Jun 26, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000230558.5
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Aug 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001241512.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
|
Likely pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 39
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004172074.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
|
|
|
Likely pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Usher syndrome type 2A
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004172075.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
|
|
|
Likely pathogenic
(Jan 01, 2015)
|
no assertion criteria provided
Method: research
|
Usher syndrome
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000598829.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Usher syndrome type 2A
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760013.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
|
|
Pathogenic
(Sep 30, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Usher syndrome type 2A
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002090852.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Pathogenic
(Aug 20, 2024)
|
no assertion criteria provided
Method: clinical testing
|
USH2A-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004116761.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The USH2A c.7595-3C>G variant is predicted to interfere with splicing. This variant has been reported to be causative for autosomal recessive Usher syndrome type 2 … (more)
The USH2A c.7595-3C>G variant is predicted to interfere with splicing. This variant has been reported to be causative for autosomal recessive Usher syndrome type 2 (Baux et al. 2007. PubMed ID: 17405132; Sloan-Heggen et al. 2016. PubMed ID: 26969326; Le Guédard-Méreuze et al. 2010. PubMed ID: 20052763). Ex vivo splicing assays showed that this variant leads to aberrant splicing (Le Guédard-Méreuze et al. 2010. PubMed ID: 20052763). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Results in gain of a new acceptor splice site in intron 40; Published minigene assays demonstrate abnormal gene splicing with insertion of intronic sequence in the open reading frame, resulting in a frameshift and premature termination of translation (PMID: 20052763); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25649381, 24944099, 27208204, 34758253, 25097241, 22135276, 27460420, 20052763, 17405132, 26969326, 28981474, 28041643, 32176120, 32581362, 31589614, 36011334, 34948090, 31816670, 35266249, 31964843, 36819107)
Comment:
The USH2A c.7595-3C>G variant is predicted to interfere with splicing. This variant has been reported to be causative for autosomal recessive Usher syndrome type 2 (Baux et al. 2007. PubMed ID: 17405132; Sloan-Heggen et al. 2016. PubMed ID: 26969326; Le Guédard-Méreuze et al. 2010. PubMed ID: 20052763). Ex vivo splicing assays showed that this variant leads to aberrant splicing (Le Guédard-Méreuze et al. 2010. PubMed ID: 20052763). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
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. |
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. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201657446, gnomAD 0.002%). This variant has been observed in individual(s) with Usher syndrome type II (PMID: 17405132, 22135276, 24944099, 25097241, 26969326). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197447). 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: 20052763). For these reasons, this variant has been classified as Pathogenic.
Comment:
Results in gain of a new acceptor splice site in intron 40; Published minigene assays demonstrate abnormal gene splicing with insertion of intronic sequence in the open reading frame, resulting in a frameshift and premature termination of translation (PMID: 20052763); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25649381, 24944099, 27208204, 34758253, 25097241, 22135276, 27460420, 20052763, 17405132, 26969326, 28981474, 28041643, 32176120, 32581362, 31589614, 36011334, 34948090, 31816670, 35266249, 31964843, 36819107)
Comment:
The USH2A c.7595-3C>G variant is predicted to interfere with splicing. This variant has been reported to be causative for autosomal recessive Usher syndrome type 2 (Baux et al. 2007. PubMed ID: 17405132; Sloan-Heggen et al. 2016. PubMed ID: 26969326; Le Guédard-Méreuze et al. 2010. PubMed ID: 20052763). Ex vivo splicing assays showed that this variant leads to aberrant splicing (Le Guédard-Méreuze et al. 2010. PubMed ID: 20052763). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Molecular findings from 537 individuals with inherited retinal disease. | Ellingford JM | Journal of medical genetics | 2016 | PMID: 27208204 |
| Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. | Sloan-Heggen CM | Human genetics | 2016 | PMID: 26969326 |
| 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 |
| Dependable and efficient clinical utility of target capture-based deep sequencing in molecular diagnosis of retinitis pigmentosa. | Wang J | Investigative ophthalmology & visual science | 2014 | PMID: 25097241 |
| Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots. | Baux D | Human mutation | 2014 | PMID: 24944099 |
| Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study. | Le Quesne Stabej P | Journal of medical genetics | 2012 | PMID: 22135276 |
| Ex vivo splicing assays of mutations at noncanonical positions of splice sites in USHER genes. | Le Guédard-Méreuze S | Human mutation | 2010 | PMID: 20052763 |
| 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 |
| 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 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs201657446 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.