ClinVar Genomic variation as it relates to human health
NM_206933.4(USH2A):c.4732C>T (p.Arg1578Cys)
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.4732C>T (p.Arg1578Cys)
Variation ID: 861348 Accession: VCV000861348.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q41 1: 216097109 (GRCh38) [ NCBI UCSC ] 1: 216270451 (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 15, 2020 Feb 14, 2024 Jan 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_206933.4:c.4732C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_996816.3:p.Arg1578Cys missense NC_000001.11:g.216097109G>A NC_000001.10:g.216270451G>A NG_009497.2:g.331340C>T - Protein change
- R1578C
- Other names
- -
- Canonical SPDI
- NC_000001.11:216097108: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 |
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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Pathogenic (3) |
criteria provided, single submitter
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Jan 13, 2024 | RCV001067861.10 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 4, 2023 | RCV001376322.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 18, 2022 | RCV002282450.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 4, 2023 | RCV003455294.1 |
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
(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: SCV001573426.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The USH2A c.4732C>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.4732C>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, PP3, PP1, PM3-S. Based on this evidence we have classified this variant as Likely Pathogenic. (less)
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Pathogenic
(Aug 18, 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: SCV002572153.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: USH2A c.4732C>T (p.Arg1578Cys) results in a non-conservative amino acid change located in the laminin G domain (IPR001791) of the encoded protein sequence. Three … (more)
Variant summary: USH2A c.4732C>T (p.Arg1578Cys) results in a non-conservative amino acid change located in the laminin G domain (IPR001791) of the encoded protein sequence. Three out of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251166 control chromosomes (gnomAD). c.4732C>T has been reported in the literature in multiple biallelic individuals affected with Usher Syndrome and/or retinitis pigmentosa (e.g. Le Quesne Stabej_2012, Jinda_2014, Pierrache_2016, Eandi_2017, Sun_2018, Karali_2019, Mansard_2021, Bahena_2022). 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. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All classified the variant as pathogenic (n=1) or likely pathogenic (n=2). 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: SCV004182205.1
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: SCV004182208.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Oct 21, 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: SCV004208143.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 13, 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: SCV001232942.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1578 of the USH2A protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1578 of the USH2A protein (p.Arg1578Cys). This variant is present in population databases (rs201529124, gnomAD 0.008%). This missense change has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 22135276, 24618324, 29142287, 29625443). 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: 861348). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely 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: SCV001924929.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 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: SCV001971959.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(Apr 17, 2023)
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no assertion criteria provided
Method: literature only
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RETINITIS PIGMENTOSA 39
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV003841033.2
First in ClinVar: Mar 18, 2023 Last updated: Apr 23, 2023 |
Comment on evidence:
In 2 Korean probands with retinitis pigmentosa (RP39; 613809), Jung et al. (2023) identified compound heterozygosity for a c.4732C-T transition in exon 22 of the … (more)
In 2 Korean probands with retinitis pigmentosa (RP39; 613809), Jung et al. (2023) identified compound heterozygosity for a c.4732C-T transition in exon 22 of the USH2A gene, resulting in an arg1578-to-cys (R1578C) substitution within the LamG 1 domain, and another missense or truncating mutation in the USH2A gene (e.g., 608400.0016). Hearing tests were not performed, but no hearing problems were reported by the probands. (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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Exome sequencing identified five novel USH2A variants in Korean patients with retinitis pigmentosa. | Jung S | Ophthalmic genetics | 2023 | PMID: 36314366 |
Unraveling the genetic complexities of combined retinal dystrophy and hearing impairment. | Bahena P | Human genetics | 2022 | PMID: 34148116 |
The Study of a 231 French Patient Cohort Significantly Extends the Mutational Spectrum of the Two Major Usher Genes MYO7A and USH2A. | Mansard L | International journal of molecular sciences | 2021 | PMID: 34948090 |
Clinical and Genetic Analysis of a European Cohort with Pericentral Retinitis Pigmentosa. | Karali M | International journal of molecular sciences | 2019 | PMID: 31877679 |
Comprehensive Molecular Screening in Chinese Usher Syndrome Patients. | Sun T | Investigative ophthalmology & visual science | 2018 | PMID: 29625443 |
Targeted next generation sequencing in Italian patients with Usher syndrome: phenotype-genotype correlations. | Eandi CM | Scientific reports | 2017 | PMID: 29142287 |
Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa. | Pierrache LH | Ophthalmology | 2016 | PMID: 26927203 |
Whole exome sequencing in Thai patients with retinitis pigmentosa reveals novel mutations in six genes. | Jinda W | Investigative ophthalmology & visual science | 2014 | PMID: 24618324 |
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 |
Text-mined citations for rs201529124 ...
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.