ClinVar Genomic variation as it relates to human health
NM_000539.3(RHO):c.403C>T (p.Arg135Trp)
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_000539.3(RHO):c.403C>T (p.Arg135Trp)
Variation ID: 13028 Accession: VCV000013028.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q22.1 3: 129530917 (GRCh38) [ NCBI UCSC ] 3: 129249760 (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 8, 2014 Oct 8, 2024 Jan 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000539.3:c.403C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000530.1:p.Arg135Trp missense NC_000003.12:g.129530917C>T NC_000003.11:g.129249760C>T NG_009115.1:g.7279C>T P08100:p.Arg135Trp - Protein change
- R135W
- Other names
- NP_000530.1:p.(Arg135Trp)
- Canonical SPDI
- NC_000003.12:129530916: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.
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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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RHO | - | - |
GRCh38 GRCh37 |
580 | 595 |
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 (1) |
no assertion criteria provided
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Apr 1, 1997 | RCV000013903.25 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 22, 2022 | RCV000013902.27 | |
Pathogenic (4) |
criteria provided, single submitter
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Jul 24, 2023 | RCV000132597.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 8, 2024 | RCV000413771.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2023 | RCV001074272.4 | |
RHO-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Aug 21, 2024 | RCV004755734.1 |
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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Pathogenic
(Sep 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 4
Affected status: yes
Allele origin:
germline
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Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Accession: SCV001443216.1
First in ClinVar: Nov 19, 2020 Last updated: Nov 19, 2020 |
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Pathogenic
(May 15, 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: SCV001239845.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 4
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521615.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.74). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013028). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:18175313, 1862076, 25101269, 28559085). A different missense change at the same codon (p.Arg135Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013024, VCV000279882). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Rod-cone dystrophy (present)
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Pathogenic
(Oct 12, 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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GeneDx
Accession: SCV000490772.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect; the variant results in the protein being retained in the ER leading to cellular apoptosis (Yu et al., … (more)
Published functional studies demonstrate a damaging effect; the variant results in the protein being retained in the ER leading to cellular apoptosis (Yu et al., 2019); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10521250, 1862076, 8841304, 18175313, 26962691, 25101269, 26794436, 21094163, 25619725, 8486634, 30635925, 29785639, 30977563, 31239368, 31054281, 31456290, 11139241, 32100970, 33576794, 1882937, 33090715, 25356976, 33781268, 33946315, 32037395, 28559085) (less)
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Pathogenic
(Jul 24, 2023)
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criteria provided, single submitter
Method: research
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Retinitis pigmentosa
Affected status: yes
Allele origin:
germline
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Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel
Accession: SCV004030293.1
First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023
Comment:
This variant was classified as Pathogenic based on ACMG criteria: PP5, PM2, PM5, PM1, PP3, PP2.
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Comment:
Clinical significance based on ACMG v2.0
Number of individuals with the variant: 1
Sex: female
Geographic origin: Portugal
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Pathogenic
(Jan 08, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001234184.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 135 of the RHO protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 135 of the RHO protein (p.Arg135Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 1862076, 18175313, 25101269, 28559085). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13028). 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 RHO protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 2023)
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criteria provided, single submitter
Method: research
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Dept Of Ophthalmology, Nagoya University
Accession: SCV004705655.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
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Pathogenic
(Apr 01, 1997)
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no assertion criteria provided
Method: literature only
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RETINITIS PUNCTATA ALBESCENS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034150.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
In 2 patients with autosomal dominant RP (RP4; 613731), Sung et al. (1991) identified an arg135-to-trp (R135W) mutation in the RHO gene. In 2 families … (more)
In 2 patients with autosomal dominant RP (RP4; 613731), Sung et al. (1991) identified an arg135-to-trp (R135W) mutation in the RHO gene. In 2 families with autosomal dominant RP, Jacobson et al. (1991) identified the R135W mutation in the RHO gene. All members of these families and of another family with an R135L mutation (180380.0011) showed loss of rod function diffusely across the visual field with some residual cone function on dark-adapted perimetry, and even at relatively young ages had undetectable rod and cone electroretinograms. In a large Sicilian pedigree with autosomal dominant RP, Pannarale et al. (1996) identified a 403C-T transition in exon 2 of the rhodopsin gene, producing an R135W mutation in the rhodopsin molecule. Patients demonstrated measurable ERG activity until at least 18 years of age, although it was reduced to 2 to 4% of normal. The rate of progression of disease was unusually high, with an average 50% loss per year of baseline ERG amplitude and visual field area. Later in the course of the disease, macular function was also severely compromised, leaving only residual central vision by the fourth decade of life. Pannarale et al. (1996) concluded that the phenotype associated with mutations at codon 135 of rhodopsin appears to have an unusually high progression rate and to yield an extremely poor prognosis. In a 4-generation Swedish family segregating autosomal dominant retinitis pigmentosa, Ponjavic et al. (1997) identified the R135W mutation. Using full-field ERG, the authors documented a severe form of RP in affected members, similar to the phenotype observed by Andreasson et al. (1992) in a family with the R135L mutation (see 180380.0011). Ponjavic et al. (1997) noted that both mutations cause the substitution of hydrophobic amino acids at codon 135, and that point mutations in this specific region of the rhodopsin molecule seem to cause an aggressive form of retinitis pigmentosa. Souied et al. (1996) screened for mutations in the rhodopsin, peripherin/RDS (179605), and ROM1 (180721) genes in a family affected with retinitis punctata albescens (136880). One member of the family showed features typical of retinitis pigmentosa. Therefore, they analyzed the apolipoprotein E (APOE; 107741) gene to elucidate the unusual intrafamilial heterogeneity. The coding sequences of the first 3 genes were analyzed with a combination of SSCP1 and direct sequence analysis. The arg135-to-trp (R135W) mutation in RHO was observed in all affected members of the family and no mutation was detected in RDS or ROM1. The epsilon-4 allele of the APOE gene appeared to cosegregate with the albescens phenotype in this family. A mother and 2 daughters had retinitis punctata albescens and the APOE4 allele. A brother of the mother had retinitis pigmentosa alone. Souied et al. (1996) reported that they had found the R135W RHO mutation in 3 (5%) of 58 subjects with autosomal dominant RP. (less)
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Pathogenic
(Apr 01, 1997)
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no assertion criteria provided
Method: literature only
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RETINITIS PIGMENTOSA 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034149.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
In 2 patients with autosomal dominant RP (RP4; 613731), Sung et al. (1991) identified an arg135-to-trp (R135W) mutation in the RHO gene. In 2 families … (more)
In 2 patients with autosomal dominant RP (RP4; 613731), Sung et al. (1991) identified an arg135-to-trp (R135W) mutation in the RHO gene. In 2 families with autosomal dominant RP, Jacobson et al. (1991) identified the R135W mutation in the RHO gene. All members of these families and of another family with an R135L mutation (180380.0011) showed loss of rod function diffusely across the visual field with some residual cone function on dark-adapted perimetry, and even at relatively young ages had undetectable rod and cone electroretinograms. In a large Sicilian pedigree with autosomal dominant RP, Pannarale et al. (1996) identified a 403C-T transition in exon 2 of the rhodopsin gene, producing an R135W mutation in the rhodopsin molecule. Patients demonstrated measurable ERG activity until at least 18 years of age, although it was reduced to 2 to 4% of normal. The rate of progression of disease was unusually high, with an average 50% loss per year of baseline ERG amplitude and visual field area. Later in the course of the disease, macular function was also severely compromised, leaving only residual central vision by the fourth decade of life. Pannarale et al. (1996) concluded that the phenotype associated with mutations at codon 135 of rhodopsin appears to have an unusually high progression rate and to yield an extremely poor prognosis. In a 4-generation Swedish family segregating autosomal dominant retinitis pigmentosa, Ponjavic et al. (1997) identified the R135W mutation. Using full-field ERG, the authors documented a severe form of RP in affected members, similar to the phenotype observed by Andreasson et al. (1992) in a family with the R135L mutation (see 180380.0011). Ponjavic et al. (1997) noted that both mutations cause the substitution of hydrophobic amino acids at codon 135, and that point mutations in this specific region of the rhodopsin molecule seem to cause an aggressive form of retinitis pigmentosa. Souied et al. (1996) screened for mutations in the rhodopsin, peripherin/RDS (179605), and ROM1 (180721) genes in a family affected with retinitis punctata albescens (136880). One member of the family showed features typical of retinitis pigmentosa. Therefore, they analyzed the apolipoprotein E (APOE; 107741) gene to elucidate the unusual intrafamilial heterogeneity. The coding sequences of the first 3 genes were analyzed with a combination of SSCP1 and direct sequence analysis. The arg135-to-trp (R135W) mutation in RHO was observed in all affected members of the family and no mutation was detected in RDS or ROM1. The epsilon-4 allele of the APOE gene appeared to cosegregate with the albescens phenotype in this family. A mother and 2 daughters had retinitis punctata albescens and the APOE4 allele. A brother of the mother had retinitis pigmentosa alone. Souied et al. (1996) reported that they had found the R135W RHO mutation in 3 (5%) of 58 subjects with autosomal dominant RP. (less)
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Pathogenic
(Aug 21, 2024)
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no assertion criteria provided
Method: clinical testing
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RHO-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005360034.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The RHO c.403C>T variant is predicted to result in the amino acid substitution p.Arg135Trp. This variant has been reported in individuals with autosomal dominant retinitis … (more)
The RHO c.403C>T variant is predicted to result in the amino acid substitution p.Arg135Trp. This variant has been reported in individuals with autosomal dominant retinitis pigmentosa (see for examples Sung et al. 1991. PubMed ID: 1862076; Beryozkin et al. 2016. PubMed ID: 26962691). Additionally, different substitutions of the same amino acid (p.Arg135Gly, p.Arg135Leu) have been reported in individuals with for retinitis pigmentosa (Bunge et al. 1993. PubMed ID: 8406457; Andreasson et al. 1992. PubMed ID: 1484692). In silico studies suggest that the substitution of the p.Arg135 codon affects endocytosis and protein interaction (Mokarzel-Falcón et al. 2008. PubMed ID: 18175313; Rakoczy et al. 2011, PubMed ID: 21094163). Given all the evidence, we interpret c.403C>T (p.Arg135Trp) as pathogenic. (less)
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pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Retinitis pigmentosa
Affected status: not provided
Allele origin:
not provided
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Department of Ophthalmology and Visual Sciences Kyoto University
Accession: SCV000172544.1
First in ClinVar: Aug 08, 2014 Last updated: Aug 08, 2014 |
Comment:
Converted during submission to Pathogenic.
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Pathogenic
(Apr 01, 2018)
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no assertion criteria provided
Method: research
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Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926670.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
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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: SCV001161242.1
First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020 |
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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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The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis. | Peter VG | PNAS nexus | 2023 | PMID: 36909829 |
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. | Stone EM | Ophthalmology | 2017 | PMID: 28559085 |
Whole exome sequencing reveals genetic predisposition in a large family with retinitis pigmentosa. | Wu J | BioMed research international | 2014 | PMID: 25101269 |
In silico study of the human rhodopsin and meta rhodopsin II/S-arrestin complexes: impact of single point mutations related to retina degenerative diseases. | Mokarzel-Falcón L | Proteins | 2008 | PMID: 18175313 |
Autosomal dominant retinitis pigmentosa with a rhodopsin mutation (Arg-135-Trp). Disease phenotype in a Swedish family. | Ponjavic V | Acta ophthalmologica Scandinavica | 1997 | PMID: 9197578 |
Autosomal-dominant retinitis pigmentosa associated with an Arg-135-Trp point mutation of the rhodopsin gene. Clinical features and longitudinal observations. | Pannarale MR | Ophthalmology | 1996 | PMID: 8841304 |
Retinitis punctata albescens associated with the Arg135Trp mutation in the rhodopsin gene. | Souied E | American journal of ophthalmology | 1996 | PMID: 8554077 |
A six-generation family with autosomal dominant retinitis pigmentosa and a rhodopsin gene mutation (arginine-135-leucine). | Andréasson S | Ophthalmic paediatrics and genetics | 1992 | PMID: 1484692 |
Retinal function and rhodopsin levels in autosomal dominant retinitis pigmentosa with rhodopsin mutations. | Jacobson SG | American journal of ophthalmology | 1991 | PMID: 1882937 |
Rhodopsin mutations in autosomal dominant retinitis pigmentosa. | Sung CH | Proceedings of the National Academy of Sciences of the United States of America | 1991 | PMID: 1862076 |
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Text-mined citations for rs104893775 ...
HelpRecord last updated Oct 13, 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.