ClinVar Genomic variation as it relates to human health
NM_206933.4(USH2A):c.14453C>T (p.Pro4818Leu)
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.14453C>T (p.Pro4818Leu)
Variation ID: 504509 Accession: VCV000504509.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q41 1: 215648657 (GRCh38) [ NCBI UCSC ] 1: 215821999 (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 Apr 9, 2018 Feb 14, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206933.4:c.14453C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996816.3:p.Pro4818Leu missense NM_206933.3:c.14453C>T NC_000001.11:g.215648657G>A NC_000001.10:g.215821999G>A NG_009497.2:g.779792C>T - Protein change
- P4818L
- Other names
- -
- Canonical SPDI
- NC_000001.11:215648656:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00010
The Genome Aggregation Database (gnomAD) 0.00011
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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USH2A | - | - |
GRCh38 GRCh37 |
6918 | 8387 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Dec 22, 2016 | RCV000613330.4 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV001040115.9 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 4, 2023 | RCV000986515.3 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 4, 2023 | RCV001376397.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 2, 2022 | RCV002506444.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 15, 2023 | RCV003155245.1 |
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
(Dec 22, 2016)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000710852.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Pro4818Leu variant in USH2A has been reported in 5 individuals with Usher syndrome and 1 individual with retinitis pigmentosa (Aller 2006, Garcia-Garcia 2 011, … (more)
The p.Pro4818Leu variant in USH2A has been reported in 5 individuals with Usher syndrome and 1 individual with retinitis pigmentosa (Aller 2006, Garcia-Garcia 2 011, Jaijo 2010, McGee 2010, Zhao 2015). Two individuals with Usher syndrome wer e confirmed to have a different truncating variant affecting the other copy of U SH2A. This variant has been identified in several populations by the Exome Aggre gation Consortium with the highest frequency of 3/16510 in South Asian chromosom es (ExAC, http://exac.broadinstitute.org; dbSNP rs143344549). However, this is low enough to be consistent with a recessive carrier frequency. Computational pr ediction tools and conservation analysis suggest that the p.Pro4818Leu variant m ay impact the protein. In summary, although additional studies are required to f ully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Usher syndrome based on its occurrence in trans with another pathogenic variant in USH2A in multiple unrelated affected individuals. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(May 28, 2019)
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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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Mendelics
Accession: SCV001135530.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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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: SCV001573520.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The USH2A c.14453C>T 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.14453C>T 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-M. Based on this evidence we have classified this variant as Likely Pathogenic. (less)
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 2A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766819.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 39 (MIM#613809) and type 2A Usher syndrome (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 17 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many individuals with autosomal recessive retinitis pigmentosa or Usher syndrome (PMIDs: 22004887, 25472526, 29899460, 30081015, 32098976). It has also been reported as likely pathogenic/pathogenic in ClinVar and Deafness Variation Database. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Mar 02, 2022)
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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: SCV002811686.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Oct 06, 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: SCV002584334.2
First in ClinVar: Oct 22, 2022 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17085681, 22004887, 30081015, 19683999, 20507924, 20591486, 25472526, 29899460, 30245926, 31589614, 34426522, 31980526, 31429209) (less)
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Pathogenic
(Feb 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844830.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: USH2A c.14453C>T (p.Pro4818Leu) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence, altering … (more)
Variant summary: USH2A c.14453C>T (p.Pro4818Leu) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence, altering a highly conserved residue (HGMD). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251372 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (6.4e-05 vs 0.011), allowing no conclusion about variant significance. c.14453C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa or Usher Syndrome (Aller_2006, Garcia-Garcia_2011, Huang_2018, Jaijo_2010, Jauregui_2020, Zhao_2015), and several 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven subitters 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
(Nov 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 39
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004183065.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely pathogenic
(Nov 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 2A
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004183066.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Likely 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: SCV004208171.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jun 17, 2022)
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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: SCV003826097.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 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: SCV001203673.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4818 of the USH2A protein (p.Pro4818Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4818 of the USH2A protein (p.Pro4818Leu). This variant is present in population databases (rs143344549, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 17085681, 22004887, 25472526, 29899460). 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: 504509). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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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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Disease asymmetry and hyperautofluorescent ring shape in retinitis pigmentosa patients. | Jauregui R | Scientific reports | 2020 | PMID: 32098976 |
Rates of Bone Spicule Pigment Appearance in Patients With Retinitis Pigmentosa Sine Pigmento. | Takahashi VKL | American journal of ophthalmology | 2018 | PMID: 30081015 |
Mutation screening of the USH2A gene in retinitis pigmentosa and USHER patients in a Han Chinese population. | Huang L | Eye (London, England) | 2018 | PMID: 29899460 |
Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland. | Zhao L | Human genetics | 2015 | PMID: 25472526 |
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 |
Microarray-based mutation analysis of 183 Spanish families with Usher syndrome. | Jaijo T | Investigative ophthalmology & visual science | 2010 | PMID: 19683999 |
Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II. | Aller E | Journal of medical genetics | 2006 | PMID: 17085681 |
Text-mined citations for rs143344549 ...
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.