Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 29568217, 2594029, 22328814, 32218800)
ClinVar Genomic variation as it relates to human health
NM_000321.3(RB1):c.2359C>T (p.Arg787Ter)
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.
Conflicting classifications of pathogenicity
Pathogenic(5); Uncertain significance(1)
Pathogenic(5); Uncertain significance(1)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000321.3(RB1):c.2359C>T (p.Arg787Ter)
Variation ID: 13073 Accession: VCV000013073.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.2 13: 48465238 (GRCh38) [ NCBI UCSC ] 13: 49039374 (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 4, 2013 Aug 11, 2024 May 20, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000321.3:c.2359C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000312.2:p.Arg787Ter nonsense NC_000013.11:g.48465238C>T NC_000013.10:g.49039374C>T NG_009009.1:g.166492C>T LRG_517:g.166492C>T LRG_517t1:c.2359C>T LRG_517p1:p.Arg787Ter - Protein change
- R787*
- Other names
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L11910:g.162237C>T
- Canonical SPDI
- NC_000013.11:48465237: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.
- -
- 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. |
|||
| RB1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3636 | 3797 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
May 20, 2024 | RCV000013948.16 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 17, 2021 | RCV000760351.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 2, 2024 | RCV000492108.4 |
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
(Nov 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000890211.4
First in ClinVar: Mar 19, 2019 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 29568217, 2594029, 22328814, 32218800) (less)
|
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Uncertain significance
(Mar 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Retinoblastoma
Affected status: yes
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV003843088.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
The RB1 c.2359C>T (p.Arg787Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. This variant … (more)
The RB1 c.2359C>T (p.Arg787Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. This variant has been identified in multiple individuals with retinoblastoma (PMID: 2594029, 34277001, 29568217, 34580403, internal data) of which at least one case was assumed to be de novo. This variant is also absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. (less)
|
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Pathogenic
(May 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Retinoblastoma
Affected status: yes
Allele origin:
germline
|
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine
Accession: SCV000087393.2
First in ClinVar: Apr 19, 2014 Last updated: Jun 02, 2024 |
Comment:
Case and Pedigree Information: BILATERAL CASES:16, UNILATERAL CASES:1, TOTAL CASES:17, PEDIGREES:17. ACMG Codes Applied:PVS1, PM2, PS4M
Number of individuals with the variant: 17
|
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Pathogenic
(May 29, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000228006.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Retinoblastoma
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000754158.6
First in ClinVar: Jun 28, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg787*) in the RB1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg787*) in the RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 2594029, 22328814, 24225018, 25602518, 26530098, 29568217). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13073). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000580773.7
First in ClinVar: Jul 01, 2017 Last updated: Aug 11, 2024 |
Comment:
The p.R787* pathogenic mutation (also known as c.2359C>T), located in coding exon 23 of the RB1 gene, results from a C to T substitution at … (more)
The p.R787* pathogenic mutation (also known as c.2359C>T), located in coding exon 23 of the RB1 gene, results from a C to T substitution at nucleotide position 2359. This changes the amino acid from an arginine to a stop codon within coding exon 23. This alteration was first characterized in a patient diagnosed with bilateral retinoblastoma at six weeks of age (Yandell DW et al. N. Engl. J. Med. 1989 Dec;321(25):1689-95). It has subsequently been identified in multiple unrelated patients and families with retinoblastoma and retinocytoma (Alonso J et al. Hum. Mutat. 2005 Jan;25:99; Taylor M et al. Hum. Mutat. 2007 Mar; 28(3):284-93; Ahani A et al. Cancer Genet. 2011 Jun;204:316-22; Abouzeid H et al. Br J Ophthalmol. 2012 Jun;96(6):884-9; He MY et al. Mol. Vis. 2014;20:545-52; Sagi M et al. Fam. Cancer. 2015 Sep;14:471-80; Singh J et al. Mol. Vis. 2016 Aug;22:1036-47; Nguyen HH et al. Mol. Vis. 2018 Mar;24:231-23). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Dec 21, 1989)
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no assertion criteria provided
Method: literature only
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RETINOBLASTOMA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034195.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In the tumor of a patient (RB-53) with bilateral retinoblastoma (180200), Yandell et al. (1989) identified a heterozygous 2498C-T transition in exon 23 of the … (more)
In the tumor of a patient (RB-53) with bilateral retinoblastoma (180200), Yandell et al. (1989) identified a heterozygous 2498C-T transition in exon 23 of the RB1 gene, resulting in an arg787-to-ter substitution. This represented a new germline mutation. (less)
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Pathogenic
(May 13, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Retinoblastoma
Affected status: yes
Allele origin:
de novo
|
Pediatric Genetics Clinic, Sheba Medical Center
Accession: SCV001712182.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Clinical Features:
Retinoblastoma (present)
Secondary finding: no
|
Comment:
Comment:
The RB1 c.2359C>T (p.Arg787Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. This variant has been identified in multiple individuals with retinoblastoma (PMID: 2594029, 34277001, 29568217, 34580403, internal data) of which at least one case was assumed to be de novo. This variant is also absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
Comment:
Case and Pedigree Information: BILATERAL CASES:16, UNILATERAL CASES:1, TOTAL CASES:17, PEDIGREES:17. ACMG Codes Applied:PVS1, PM2, PS4M
Comment:
This sequence change creates a premature translational stop signal (p.Arg787*) in the RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 2594029, 22328814, 24225018, 25602518, 26530098, 29568217). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13073). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R787* pathogenic mutation (also known as c.2359C>T), located in coding exon 23 of the RB1 gene, results from a C to T substitution at nucleotide position 2359. This changes the amino acid from an arginine to a stop codon within coding exon 23. This alteration was first characterized in a patient diagnosed with bilateral retinoblastoma at six weeks of age (Yandell DW et al. N. Engl. J. Med. 1989 Dec;321(25):1689-95). It has subsequently been identified in multiple unrelated patients and families with retinoblastoma and retinocytoma (Alonso J et al. Hum. Mutat. 2005 Jan;25:99; Taylor M et al. Hum. Mutat. 2007 Mar; 28(3):284-93; Ahani A et al. Cancer Genet. 2011 Jun;204:316-22; Abouzeid H et al. Br J Ophthalmol. 2012 Jun;96(6):884-9; He MY et al. Mol. Vis. 2014;20:545-52; Sagi M et al. Fam. Cancer. 2015 Sep;14:471-80; Singh J et al. Mol. Vis. 2016 Aug;22:1036-47; Nguyen HH et al. Mol. Vis. 2018 Mar;24:231-23). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 29568217, 2594029, 22328814, 32218800)
Comment:
The RB1 c.2359C>T (p.Arg787Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. This variant has been identified in multiple individuals with retinoblastoma (PMID: 2594029, 34277001, 29568217, 34580403, internal data) of which at least one case was assumed to be de novo. This variant is also absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic.
Comment:
Case and Pedigree Information: BILATERAL CASES:16, UNILATERAL CASES:1, TOTAL CASES:17, PEDIGREES:17. ACMG Codes Applied:PVS1, PM2, PS4M
Comment:
This sequence change creates a premature translational stop signal (p.Arg787*) in the RB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 2594029, 22328814, 24225018, 25602518, 26530098, 29568217). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13073). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R787* pathogenic mutation (also known as c.2359C>T), located in coding exon 23 of the RB1 gene, results from a C to T substitution at nucleotide position 2359. This changes the amino acid from an arginine to a stop codon within coding exon 23. This alteration was first characterized in a patient diagnosed with bilateral retinoblastoma at six weeks of age (Yandell DW et al. N. Engl. J. Med. 1989 Dec;321(25):1689-95). It has subsequently been identified in multiple unrelated patients and families with retinoblastoma and retinocytoma (Alonso J et al. Hum. Mutat. 2005 Jan;25:99; Taylor M et al. Hum. Mutat. 2007 Mar; 28(3):284-93; Ahani A et al. Cancer Genet. 2011 Jun;204:316-22; Abouzeid H et al. Br J Ophthalmol. 2012 Jun;96(6):884-9; He MY et al. Mol. Vis. 2014;20:545-52; Sagi M et al. Fam. Cancer. 2015 Sep;14:471-80; Singh J et al. Mol. Vis. 2016 Aug;22:1036-47; Nguyen HH et al. Mol. Vis. 2018 Mar;24:231-23). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutational screening of germline RB1 gene in Vietnamese patients with retinoblastoma reveals three novel mutations. | Nguyen HH | Molecular vision | 2018 | PMID: 29568217 |
| Next-generation sequencing-based method shows increased mutation detection sensitivity in an Indian retinoblastoma cohort. | Singh J | Molecular vision | 2016 | PMID: 27582626 |
| Advantages of a next generation sequencing targeted approach for the molecular diagnosis of retinoblastoma. | Grotta S | BMC cancer | 2015 | PMID: 26530098 |
| Genetic screening in patients with Retinoblastoma in Israel. | Sagi M | Familial cancer | 2015 | PMID: 25754945 |
| Mutation spectrum of RB1 gene in unilateral retinoblastoma cases from Tunisia and correlations with clinical features. | Ayari-Jeridi H | PloS one | 2015 | PMID: 25602518 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| Screening of RB1 gene mutations in Chinese patients with retinoblastoma and preliminary exploration of genotype-phenotype correlations. | He MY | Molecular vision | 2014 | PMID: 24791139 |
| Spectrum of RB1 mutations identified in 403 retinoblastoma patients. | Price EA | Journal of medical genetics | 2014 | PMID: 24225018 |
| Phenotypic variability of retinocytomas: preregression and postregression growth patterns. | Abouzeid H | The British journal of ophthalmology | 2012 | PMID: 22328814 |
| RB1 gene mutations in Iranian patients with retinoblastoma: report of four novel mutations. | Ahani A | Cancer genetics | 2011 | PMID: 21763628 |
| Genotype-phenotype correlations in hereditary familial retinoblastoma. | Taylor M | Human mutation | 2007 | PMID: 17096365 |
| Identification of 26 new constitutional RB1 gene mutations in Spanish, Colombian, and Cuban retinoblastoma patients. | Alonso J | Human mutation | 2005 | PMID: 15605413 |
| Oncogenic point mutations in the human retinoblastoma gene: their application to genetic counseling. | Yandell DW | The New England journal of medicine | 1989 | PMID: 2594029 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RB1 | - | - | - | - |
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Text-mined citations for rs137853293 ...
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 Sep 29, 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.