ClinVar Genomic variation as it relates to human health
NM_206933.4(USH2A):c.12067-2A>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.12067-2A>G
Variation ID: 48390 Accession: VCV000048390.48
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q41 1: 215680378 (GRCh38) [ NCBI UCSC ] 1: 215853720 (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 Jan 9, 2017 Apr 15, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206933.4:c.12067-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NC_000001.11:g.215680378T>C NC_000001.10:g.215853720T>C NG_009497.2:g.748071A>G - Protein change
- Other names
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- Canonical SPDI
- NC_000001.11:215680377: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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00008
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
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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 | 8386 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000412841.36 | |
Pathogenic (1) |
criteria provided, single submitter
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May 13, 2013 | RCV000390593.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000666727.11 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 16, 2023 | RCV000983997.14 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 23, 2019 | RCV001003259.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 19, 2018 | RCV001073917.8 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV001271128.13 |
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
(May 10, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000341017.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Oct 31, 2018)
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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: SCV000893284.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(May 13, 2013)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000065408.6
First in ClinVar: May 03, 2013 Last updated: Dec 15, 2018 |
Comment:
The 12067-2A>G variant in USH2A has been reported in five individuals with Usher syndrome type 2, one individual with autosomal recessive retinitis pigmentosa a nd … (more)
The 12067-2A>G variant in USH2A has been reported in five individuals with Usher syndrome type 2, one individual with autosomal recessive retinitis pigmentosa a nd one individual with congenital sensorineural hearing loss (Sandberg 2008, Aus lender 2008, Garcia-Garcia 2011, LMM unpublished data). Four of these probands w ere homozygous or compound heterozygous. Segregation of this variant with disea se was demonstrated in two affected family members (Auslender 2008). In addition , this variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or ab sent protein. In summary, this variant meets our criteria to be classified as pa thogenic. (less)
Number of individuals with the variant: 2
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Pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 2A
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV002060347.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_206933.2(USH2A):c.12067-2A>G is a canonical splice variant classified as pathogenic in the context of USH2A-related disorders. c.12067-2A>G has been observed in cases with relevant disease (PMID: … (more)
NM_206933.2(USH2A):c.12067-2A>G is a canonical splice variant classified as pathogenic in the context of USH2A-related disorders. c.12067-2A>G has been observed in cases with relevant disease (PMID: 27460420, 18452394, 22004887). Functional assessments of this variant are not available in the literature. c.12067-2A>G has been observed in population frequency databases (gnomAD: AMR 0.04%). In summary, NM_206933.2(USH2A):c.12067-2A>G is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Apr 04, 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: SCV000490873.4
First in ClinVar: Jan 09, 2017 Last updated: Apr 15, 2023 |
Comment:
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is … (more)
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 32531858, 34315337, 25525159, 25404053, 28981474, 26850479, 29490346, 30190494, 31456290, 34426522, 31589614, 32037395, 18641288, 22004887, 34948090, 34148116, 35266249, 18452394) (less)
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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: SCV004173919.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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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: SCV004173921.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Pathogenic
(Oct 16, 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: SCV004208172.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 12, 2020)
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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: SCV002020850.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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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: SCV000933043.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 61 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 61 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs397517978, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with Usher syndrome (PMID: 18452394, 22004887, 25404053, 28981474). 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: 48390). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 19, 2018)
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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: SCV001239482.1
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: SCV001573489.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The USH2A c.12067-2A>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.12067-2A>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: PVS1, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. (less)
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Pathogenic
(Sep 01, 2022)
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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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3billion
Accession: SCV002572967.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Canonical splice site is predicted to alter … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000048390 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Retinal dystrophy (present) , Hearing impairment (present) , Hearing impairment (present)
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Pathogenic
(Oct 01, 2021)
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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: SCV002062872.14
First in ClinVar: Jan 29, 2022 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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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: SCV001161341.1
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: SCV001451979.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
The Genetics of Usher Syndrome in the Israeli and Palestinian Populations. | Khalaileh A | Investigative ophthalmology & visual science | 2018 | PMID: 29490346 |
The Genetic Basis of Pericentral Retinitis Pigmentosa-A Form of Mild Retinitis Pigmentosa. | Comander J | Genes | 2017 | PMID: 28981474 |
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 |
Targeted next generation sequencing for molecular diagnosis of Usher syndrome. | Aparisi MJ | Orphanet journal of rare diseases | 2014 | PMID: 25404053 |
Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations. | Garcia-Garcia G | Orphanet journal of rare diseases | 2011 | PMID: 22004887 |
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 |
Four USH2A founder mutations underlie the majority of Usher syndrome type 2 cases among non-Ashkenazi Jews. | Auslender N | Genetic testing | 2008 | PMID: 18452394 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A | - | - | - | - |
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Text-mined citations for rs397517978 ...
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.