ClinVar Genomic variation as it relates to human health
NM_000321.3(RB1):c.1981C>T (p.Arg661Trp)
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.1981C>T (p.Arg661Trp)
Variation ID: 13087 Accession: VCV000013087.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.2 13: 48459708 (GRCh38) [ NCBI UCSC ] 13: 49033844 (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 May 1, 2024 Oct 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000321.3:c.1981C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000312.2:p.Arg661Trp missense NC_000013.11:g.48459708C>T NC_000013.10:g.49033844C>T NG_009009.1:g.160962C>T LRG_517:g.160962C>T LRG_517t1:c.1981C>T P06400:p.Arg661Trp - Protein change
- Other names
- R661W
- L11910:g.156713C>T
- Canonical SPDI
- NC_000013.11:48459707:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- loss_of_function_variant Sequence Ontology [SO:0002054]
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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 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
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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RB1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3316 | 3467 |
Conditions - Germline
Condition
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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 (7) |
criteria provided, multiple submitters, no conflicts
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Oct 25, 2023 | RCV000013962.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763335.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 23, 2023 | RCV000790652.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 21, 2022 | RCV000492717.12 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV000510137.9 |
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
(Nov 18, 2013)
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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: SCV000227619.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Dec 15, 2020)
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criteria provided, single submitter
Method: research
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Retinoblastoma
Affected status: yes
Allele origin:
germline
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Department of Pediatrics, Memorial Sloan Kettering Cancer Center
Accession: SCV001478170.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
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Pathogenic
(Jul 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinoblastoma
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556662.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
Comment:
This variant has been shown to be associated with the methylation status at CpG85 in RB1 intron 2 that is differentially methylated depending on parent … (more)
This variant has been shown to be associated with the methylation status at CpG85 in RB1 intron 2 that is differentially methylated depending on parent -of -origin. Paternally transmitted mutation has low residual activity mimics a null mutation leading to the development of retinoblastoma. (less)
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Pathogenic
(Jan 23, 2023)
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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: SCV003194892.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17960112, 9671401, 15643604, 18677112, 29568217, 34190019, 9342358, 1352883, 28575107, 12541220, 16269091, 9632788, 23532519, 16449662, 29662154, 34294096, 34277001, 34645364, 35960463, 36274096, 33466343, Day alan_2006_Review, 28724667, 34308366, 31980526, 9311732, 26925970, 10486322, 17096365, 24225018) (less)
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Pathogenic
(Sep 30, 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: SCV000551831.10
First in ClinVar: Jun 28, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 661 of the RB1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 661 of the RB1 protein (p.Arg661Trp). This variant is present in population databases (rs137853294, gnomAD 0.01%). This variant has been reported in many individuals affected with retinoblastoma (PMID: 12541220, 16269091, 23532519, 28575107, 24225018). It has been reported to segregate with retinoblastoma in multiple families (PMID: 1352883, 26925970, 17096365). While all tested affected individuals in the families had this variant, penetrance was reduced in comparison to truncating variants in RB1 seen in other families, with relatively mild phenotypic expression observed in some cases. Penetrance appears to be lower when this variant is inherited from the mother than from the father (PMID: 26925970). ClinVar contains an entry for this variant (Variation ID: 13087). 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 RB1 protein function. Experimental studies have shown that this missense change has partial activity. It retains some ability to suppress retinoblastoma development, but is unstable with temperature-sensitive pocket protein-binding activity and defective in several aspects of cell cycle control (PMID: 18677112, 18682685, 10486322, 16449662, 15643604, 9632788). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 21, 2022)
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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: SCV000580810.6
First in ClinVar: Jul 01, 2017 Last updated: May 01, 2024 |
Comment:
The p.R661W pathogenic mutation with reduced penetrance (also known as c.1981C>T), located in coding exon 20 of the RB1 gene, results from a C to … (more)
The p.R661W pathogenic mutation with reduced penetrance (also known as c.1981C>T), located in coding exon 20 of the RB1 gene, results from a C to T substitution at nucleotide position 1981. The arginine at codon 661 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in several RB families showing reduced penetrance where there are some individuals who are unaffected carriers; where some have unilateral RB; where some have bilateral RB; and some have regressed RB tumors (Onadim Z et al. Proc. Natl. Acad. Sci. U.S.A.. 1992 Jul;89:6177-81; Dommering CJ et al. J. Med. Genet. 2014 Jun;51:366-74; Eloy P et al. PLoS Genet. 2016 Feb;12:e1005888). In another study, the p.R661W pathogenic mutation accounted for approximately 3% (7/235) of unrelated retinoblastoma probands with germline RB1 mutations and approximately 13% (4/30) of germline mutations identified in probands with unilateral retinoblastoma (Richter S et al. Am. J. Hum. Genet. 2003 Feb;72:253-69). In addition, the p.R661W alteration has been shown to result in reduced, but not abolished, retinoblastoma protein activity (Whitaker LL et al. Mol. Cell. Biol. 1998 Jul;18:4032-42) and confers a decreased, albeit significant tumor risk (DiCiommo D et al. Semin. Cancer Biol. 2000 Aug;10:255-69). In a recent study including ten families with the p.R661W alteration, authors reported that if this alteration was maternally inherited the probability of being affected with RB was just under 10% whereas if this alteration was paternally inherited the probability of being affected with RB was almost 68%. They speculate that this parent-of-origin effect is due to maternal imprinting of an internal promoter which produces an alternative RB1 transcript and may contribute to the reduced penetrance of this mutation (Eloy P et al. PLoS Genet. 2016 Feb;12:e1005888; Kanber D et al. PLoS Genet. 2009 Dec;5:e1000790). Based on the supporting evidence, p.R661W is interpreted as a disease-causing mutation with reduced penetrance. (less)
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Malignant tumor of urinary bladder
Retinoblastoma Small cell lung carcinoma Bone osteosarcoma
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894012.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinoblastoma
Affected status: yes
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV004171512.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Comment:
The RB1 c.1981C>T (p.Arg661Trp) missense change has a maximum non-founder subpopulation frequency of 0.0060% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been identified in individuals … (more)
The RB1 c.1981C>T (p.Arg661Trp) missense change has a maximum non-founder subpopulation frequency of 0.0060% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been identified in individuals with retinoblastoma (PMID: 12541220, 16269091, 23532519, 24225018, 28575107) and has been found to segregate with disease in affected family members (PMID: 1352883, 26925970, 17096365). Interestingly, penetrance appears to be reduced when compared to truncating variants in RB1. It is thought to be associated with differential penetrance based on the sex of the transmitted parent, where paternally inherited alleles appear to show increased penetrance (PMID: 26925970). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies have shown that this variant is partially functional (PMID: 9632788, 10486322, 15643604, 16449662, 18677112, 18682685). In summary, this variant meets criteria to be classified as pathogenic. (less)
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Pathogenic
(Oct 01, 1999)
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no assertion criteria provided
Method: literature only
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RETINOBLASTOMA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034209.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 families with an unusual low-penetrance phenotype of retinoblastoma (180200), with many individuals carrying the gene being unaffected, unilaterally affected, or with evidence of … (more)
In 2 families with an unusual low-penetrance phenotype of retinoblastoma (180200), with many individuals carrying the gene being unaffected, unilaterally affected, or with evidence of spontaneously regressed tumors, Onadim et al. (1992) found mutations in exon 20 of RB1. (Also see 614041.0020.) In 1 family, a C-to-T transition in codon 661 converted an arginine (CGG) to tryptophan (TGG) codon. The incomplete penetrance might indicate that this single amino acid change modified protein structure/function such that tumorigenesis was not inevitable. Cowell and Bia (1998) pointed out that Lohmann et al. (1994) identified the same codon-661 mutation in 2 families with low penetrance. Cowell and Bia (1998) referred to their unpublished observations, identifying the same mutation in another family where both the 2 affected children and the unaffected father carried the arg661-to-trp (R661W) mutation. Otterson et al. (1999) stated that 9 families with incomplete penetrance of familial retinoblastoma and carrying a R661W mutation had been reported. Their studies of this mutation demonstrated that the mutation is temperature-sensitive. (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: SCV000087376.1
First in ClinVar: Apr 19, 2014 Last updated: Apr 19, 2014 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Vulvar adenocarcinoma of mammary gland type
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Genome Sciences Centre, British Columbia Cancer Agency
Accession: SCV000598654.1
First in ClinVar: Oct 25, 2017 Last updated: Oct 25, 2017 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Retinoblastoma
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002075237.2
First in ClinVar: Feb 13, 2022 Last updated: Jan 07, 2023 |
Comment:
Variant classified as Pathogenic and reported on 08-06-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant classified as Pathogenic and reported on 08-06-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Phenotypic abnormality (present) , Family history (present)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: male
Method: Single Gene Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2021-08-06
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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loss_of_function_variant
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Genome Sciences Centre, British Columbia Cancer Agency
Accession: SCV000598654.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Detection and genomic characterization of a mammary-like adenocarcinoma. | Grewal JK | Cold Spring Harbor molecular case studies | 2017 | PMID: 28877932 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. | Sun J | Clinical cancer research : an official journal of the American Association for Cancer Research | 2017 | PMID: 28724667 |
Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling. | Tomar S | PloS one | 2017 | PMID: 28575107 |
RB1 mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients. | Dommering CJ | Journal of medical genetics | 2014 | PMID: 24688104 |
Spectrum of RB1 mutations identified in 403 retinoblastoma patients. | Price EA | Journal of medical genetics | 2014 | PMID: 24225018 |
Screening of RB1 alterations in Brazilian patients with retinoblastoma and relatives with retinoma: phenotypic and genotypic associations. | Barbosa RH | Investigative ophthalmology & visual science | 2013 | PMID: 23532519 |
The human retinoblastoma gene is imprinted. | Kanber D | PLoS genetics | 2009 | PMID: 20041224 |
Comment on "Lowpenetrant RB allele in small-cell cancer shows geldanamycin instability and discordant expression with mutant ras" by Park et al. | Harbour JW | Cell cycle (Georgetown, Tex.) | 2008 | PMID: 18682685 |
Low-penetrant RB allele in small-cell cancer shows geldanamycin instability and discordant expression with mutant ras. | Park Y | Cell cycle (Georgetown, Tex.) | 2008 | PMID: 18677112 |
Genotype-phenotype correlations in hereditary familial retinoblastoma. | Taylor M | Human mutation | 2007 | PMID: 17096365 |
An E2F binding-deficient Rb1 protein partially rescues developmental defects associated with Rb1 nullizygosity. | Sun H | Molecular and cellular biology | 2006 | PMID: 16449662 |
RB1 gene mutation up-date, a meta-analysis based on 932 reported mutations available in a searchable database. | Valverde JR | BMC genetics | 2005 | PMID: 16269091 |
A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity. | Sánchez-Sánchez F | Human mutation | 2005 | PMID: 15643604 |
Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. | Richter S | American journal of human genetics | 2003 | PMID: 12541220 |
Retinoblastoma: the disease, gene and protein provide critical leads to understand cancer. | DiCiommo D | Seminars in cancer biology | 2000 | PMID: 10966849 |
Temperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families. | Otterson GA | American journal of human genetics | 1999 | PMID: 10486322 |
A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype. | Cowell JK | Oncogene | 1998 | PMID: 9671401 |
Growth suppression by an E2F-binding-defective retinoblastoma protein (RB): contribution from the RB C pocket. | Whitaker LL | Molecular and cellular biology | 1998 | PMID: 9632788 |
Spectrum of small length germline mutations in the RB1 gene. | Lohmann DR | Human molecular genetics | 1994 | PMID: 7881418 |
Oncogenic point mutations in exon 20 of the RB1 gene in families showing incomplete penetrance and mild expression of the retinoblastoma phenotype. | Onadim Z | Proceedings of the National Academy of Sciences of the United States of America | 1992 | PMID: 1352883 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RB1 | - | - | - | - |
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Text-mined citations for rs137853294 ...
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.