This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 15 of the RHO protein (p.Asn15Ser). 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: 8353500, 9483582). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13042). 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 95%. Experimental studies have shown that this missense change affects RHO function (PMID: 31100078). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000539.3(RHO):c.44A>G (p.Asn15Ser)
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.
(8)
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000539.3(RHO):c.44A>G (p.Asn15Ser)
Variation ID: 13042 Accession: VCV000013042.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q22.1 3: 129528777 (GRCh38) [ NCBI UCSC ] 3: 129247620 (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 Dec 28, 2024 Jan 11, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000539.3:c.44A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000530.1:p.Asn15Ser missense NC_000003.12:g.129528777A>G NC_000003.11:g.129247620A>G NG_009115.1:g.5139A>G P08100:p.Asn15Ser - Protein change
- N15S
- Other names
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- Canonical SPDI
- NC_000003.12:129528776:A:G
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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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- 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. |
|||
| RHO | - | - |
GRCh38 GRCh37 |
602 | 617 | |
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 (2) |
criteria provided, single submitter
|
Sep 1, 2020 | RCV000013917.25 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV000132598.1 | |
| Pathogenic (4) |
criteria provided, single submitter
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Jan 11, 2024 | RCV001203907.11 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2018 | RCV004814894.1 |
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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|---|---|---|---|---|---|
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Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001375089.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 15 of the RHO protein (p.Asn15Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 15 of the RHO protein (p.Asn15Ser). 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: 8353500, 9483582). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13042). 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 95%. Experimental studies have shown that this missense change affects RHO function (PMID: 31100078). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
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Pathogenic
(Sep 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 4
Affected status: yes
Allele origin:
germline
|
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Accession: SCV001443194.1
First in ClinVar: Nov 19, 2020 Last updated: Nov 19, 2020 |
Zygosity: Single Heterozygote
|
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Likely pathogenic
(Jan 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV005072360.1
First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024 |
|
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Pathogenic
(Nov 01, 1993)
|
no assertion criteria provided
Method: literature only
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RETINITIS PIGMENTOSA 4
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034164.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015 |
Comment on evidence:
Kranich et al. (1993) used single-strand conformation polymorphism (SSCP) to detect altered PCR products of rhodopsin coding sequences in a large Australian pedigree with the … (more)
Kranich et al. (1993) used single-strand conformation polymorphism (SSCP) to detect altered PCR products of rhodopsin coding sequences in a large Australian pedigree with the 'sectorial' form of autosomal dominant RP (RP4; 613731). Direct sequencing demonstrated an A-to-G transition at codon 15 that predicted a change from asparagine to serine. Patients in this family demonstrated an asymmetric regional distribution of pigmentary changes and visual field loss with a relatively mild form of the disease and good central visual acuity into the fourth decade. 'Sector' RP has been described in patients with the following mutations: thr17-to-met (180380.0006), pro23-to-his (180380.0001), thr58-to-arg (180380.0004), gly106-to-arg (180380.0025), and gly182-to-ser (180380.0021). Sullivan et al. (1993) described a 5-generation Australian family in which retinitis pigmentosa was associated with an inferior distribution of retinal pigmentary changes and predominantly superior visual field loss with relative preservation of electroretinographic amplitudes and good vision. The mutation was found to be in codon 15 of exon 1 where a single bp transversion (AAT to AGT) led to a serine-for-asparagine substitution. The mutation altered a glycosylation site in the intradiscal portion of the rhodopsin molecule. Inspection of the pedigrees published by Kranich et al. (1993) and Sullivan et al. (1993) indicates identity; these reports do not represent recurrent mutation. (less)
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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, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001925349.1 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: not provided
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Retinitis pigmentosa
Affected status: not provided
Allele origin:
not provided
|
Department of Ophthalmology and Visual Sciences Kyoto University
Accession: SCV000172545.1
First in ClinVar: Aug 08, 2014 Last updated: Aug 08, 2014 |
Comment:
Converted during submission to Pathogenic.
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954106.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
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: SCV001969414.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
Comment:
Comment:
Converted during submission to 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 replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 15 of the RHO protein (p.Asn15Ser). 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: 8353500, 9483582). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13042). 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 95%. Experimental studies have shown that this missense change affects RHO function (PMID: 31100078). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Converted during submission to Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis. | Panneman DM | Frontiers in cell and developmental biology | 2023 | PMID: 36819107 |
| Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy. | Karali M | Scientific reports | 2022 | PMID: 36460718 |
| Panel-based genetic testing for inherited retinal disease screening 176 genes. | Sheck LHN | Molecular genetics & genomic medicine | 2021 | PMID: 33749171 |
| Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9-year period. | Weisschuh N | Human mutation | 2020 | PMID: 32531858 |
| Sector retinitis pigmentosa: Report of ten cases and a review of the literature. | Coussa RG | Molecular vision | 2019 | PMID: 31908405 |
| Comparison of the molecular properties of retinitis pigmentosa P23H and N15S amino acid replacements in rhodopsin. | Mitchell J | PloS one | 2019 | PMID: 31100078 |
| Characterizing variants of unknown significance in rhodopsin: A functional genomics approach. | Wan A | Human mutation | 2019 | PMID: 30977563 |
| Toward the Mutational Landscape of Autosomal Dominant Retinitis Pigmentosa: A Comprehensive Analysis of 258 Spanish Families. | Martin-Merida I | Investigative ophthalmology & visual science | 2018 | PMID: 29847639 |
| Retinitis pigmentosa mutants provide insight into the role of the N-terminal cap in rhodopsin folding, structure, and function. | Opefi CA | The Journal of biological chemistry | 2013 | PMID: 24106275 |
| Analysis of disease-linked rhodopsin mutations based on structure, function, and protein stability calculations. | Rakoczy EP | Journal of molecular biology | 2011 | PMID: 21094163 |
| Visual function in retinitis pigmentosa related to a codon 15 rhodopsin gene mutation. | Yoshii M | Ophthalmic research | 1998 | PMID: 9483582 |
| Autosomal dominant 'sector' retinitis pigmentosa due to a point mutation predicting an Asn-15-Ser substitution of rhodopsin. | Kranich H | Human molecular genetics | 1993 | PMID: 8353500 |
| A new codon 15 rhodopsin gene mutation in autosomal dominant retinitis pigmentosa is associated with sectorial disease. | Sullivan LJ | Archives of ophthalmology (Chicago, Ill. : 1960) | 1993 | PMID: 8240107 |
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Text-mined citations for rs104893786 ...
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 Dec 28, 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.