ClinVar Genomic variation as it relates to human health
NM_000321.3(RB1):c.1363C>T (p.Arg455Ter)
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_000321.3(RB1):c.1363C>T (p.Arg455Ter)
Variation ID: 126837 Accession: VCV000126837.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.2 13: 48379624 (GRCh38) [ NCBI UCSC ] 13: 48953760 (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 19, 2014 May 1, 2024 Nov 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000321.3:c.1363C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000312.2:p.Arg455Ter nonsense NC_000013.11:g.48379624C>T NC_000013.10:g.48953760C>T NG_009009.1:g.80878C>T LRG_517:g.80878C>T LRG_517t1:c.1363C>T LRG_517p1:p.Arg455Ter - Protein change
- R455*
- Other names
- L11910:g.76460C>T
- Canonical SPDI
- NC_000013.11:48379623: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.
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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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RB1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3316 | 3468 |
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Jul 16, 2021 | RCV000486601.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 10, 2023 | RCV000492246.5 | |
Pathogenic (3) |
criteria provided, single submitter
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Nov 21, 2023 | RCV000114729.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2022 | RCV003156072.1 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV003332117.1 |
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
(Jul 16, 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: SCV000568220.6
First in ClinVar: Apr 27, 2017 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; This … (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; This variant is associated with the following publications: (PMID: 8968104, 24791139, 8178820, 25151137, 17205527, 23532519, 20059380, 10671068, 17960112, 28575107, 27582626, 8651278, 25602518, 22278416, 12541220, 8346255, 14769601, 25525159, 25928201, 24347427, 16269091, 1352398, 17096365, 15605413, 11317357, 15884040, 14722923, 19280657, 25712084, 23981928, 16343894, 22180099, 28803391, 33456302, 24810223, 22219649) (less)
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Pathogenic
(Apr 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000580762.7
First in ClinVar: Jul 01, 2017 Last updated: May 01, 2024 |
Comment:
The p.R455* pathogenic mutation (also known as c.1363C>T), located in coding exon 14 of the RB1 gene, results from a C to T substitution at … (more)
The p.R455* pathogenic mutation (also known as c.1363C>T), located in coding exon 14 of the RB1 gene, results from a C to T substitution at nucleotide position 1363. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration has been identified in multiple individuals with both unilateral and bilateral retinoblastoma (Lohmann DR et al. Am. J. Hum. Genet. 1996 May;58(5):940-9; Saliminejad K et al. J. Genet. 2013 May;92(2):e36-40; He MY et al. Mol. Vis. 2014 Apr; 20:545-52; Amitrano S et al. Eur. J. Hum. Genet. 2015 Nov;23(11): 1523-30); Yousef YA et al. Fam. Cancer. 2018 Apr;17(2):261-268). Additionally, this alteration has been reported in a family where two siblings with bilateral retinoblastoma were both found to be heterozygous, but their mother, who had unilateral retinoblastoma, was determined to be mosaic (Rushlow D et al. Hum. Mutat. 2009 May; 30(5):842-51). 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
(Nov 22, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000703952.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 15, 2018 |
Sex: mixed
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Pathogenic
(Dec 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
de novo
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Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV003845267.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Clinical Features:
Absent speech (present) , Autistic behavior (present) , Atypical behavior (present) , Deeply set eye (present) , Delayed speech and language development (present) , Joint … (more)
Absent speech (present) , Autistic behavior (present) , Atypical behavior (present) , Deeply set eye (present) , Delayed speech and language development (present) , Joint laxity (present) , Prominent forehead (present) , Retinoblastoma (present) , Short attention span (present) (less)
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Pathogenic
(Nov 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinoblastoma
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000629277.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg455*) 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.Arg455*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with retinoblastoma (PMID: 8651278, 17096365, 20059380, 25928201, 27582626, 28575107). 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: 126837). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 16, 2013)
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no assertion criteria provided
Method: research
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Retinoblastoma
Affected status: yes
Allele origin:
somatic
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Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine
Accession: SCV000087397.1
First in ClinVar: Apr 19, 2014 Last updated: Apr 19, 2014 |
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Likely pathogenic
(Jul 14, 2015)
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no assertion criteria provided
Method: literature only
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Retinoblastoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000505675.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Malignant tumor of urinary bladder
Affected status: yes
Allele origin:
somatic
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Laboratory of Urology, Hospital Clinic de Barcelona
Accession: SCV004040591.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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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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Mutational analysis of the RB1 gene and the inheritance patterns of retinoblastoma in Jordan. | Yousef YA | Familial cancer | 2018 | PMID: 28803391 |
Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling. | Tomar S | PloS one | 2017 | PMID: 28575107 |
Next-generation sequencing-based method shows increased mutation detection sensitivity in an Indian retinoblastoma cohort. | Singh J | Molecular vision | 2016 | PMID: 27582626 |
Targeted next generation sequencing of RB1 gene for the molecular diagnosis of Retinoblastoma. | Devarajan B | BMC cancer | 2015 | PMID: 25928201 |
Next generation sequencing in sporadic retinoblastoma patients reveals somatic mosaicism. | Amitrano S | European journal of human genetics : EJHG | 2015 | PMID: 25712084 |
Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
Screening of RB1 gene mutations in Chinese patients with retinoblastoma and preliminary exploration of genotype-phenotype correlations. | He MY | Molecular vision | 2014 | PMID: 24791139 |
Rapid detection of RB1 recurrent mutations in retinoblastoma by ARMS-PCR. | Saliminejad K | Journal of genetics | 2013 | PMID: 23981928 |
Mutational analysis of the RB1 gene in Moroccan patients with retinoblastoma. | Abidi O | Molecular vision | 2011 | PMID: 22219649 |
A c.1363C>T (p.R455X) nonsense mutation of RB1 gene in a southern Chinese retinoblastoma pedigree. | Chen CY | Genetic testing and molecular biomarkers | 2010 | PMID: 20059380 |
Detection of mosaic RB1 mutations in families with retinoblastoma. | Rushlow D | Human mutation | 2009 | PMID: 19280657 |
Genotype-phenotype correlations in hereditary familial retinoblastoma. | Taylor M | Human mutation | 2007 | PMID: 17096365 |
Spectrum of germline RB1 gene mutations in Spanish retinoblastoma patients: Phenotypic and molecular epidemiological implications. | Alonso J | Human mutation | 2001 | PMID: 11317357 |
The spectrum of RB1 germ-line mutations in hereditary retinoblastoma. | Lohmann DR | American journal of human genetics | 1996 | PMID: 8651278 |
http://docm.genome.wustl.edu/variants/ENST00000267163:c.1363C>T | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RB1 | - | - | - | - |
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Text-mined citations for rs121913302 ...
HelpRecord last updated May 01, 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.