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NM_000321.2(RB1):c.1981C>T (p.Arg661Trp)

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Interpretation:
Pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
7 (Most recent: Feb 26, 2020)
Last evaluated:
Nov 19, 2019
Accession:
VCV000013087.5
Variation ID:
13087
Description:
single nucleotide variant
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NM_000321.2(RB1):c.1981C>T (p.Arg661Trp)

Allele ID
28126
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
13q14.2
Genomic location
13: 48459708 (GRCh38) GRCh38 UCSC
13: 49033844 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000013.10:g.49033844C>T
NC_000013.11:g.48459708C>T
LRG_517t1:c.1981C>T LRG_517p1:p.Arg661Trp
... more HGVS
Protein change
-
Other names
R661W
L11910:g.156713C>T
Canonical SPDI
NC_000013.11:48459707:C:T
Functional consequence
loss_of_function_variant [Sequence Ontology SO:0002054]
Global minor allele frequency (GMAF)
0.00020 (T)

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00002
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00001
Links
ClinGen: CA026417
UniProtKB: P06400#VAR_005582
OMIM: 614041.0019
dbSNP: rs137853294
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 3 criteria provided, single submitter Nov 19, 2019 RCV000013962.9
Pathogenic 1 criteria provided, single submitter Mar 30, 2018 RCV000492717.2
Pathogenic 1 criteria provided, single submitter Oct 31, 2018 RCV000763335.1
Pathogenic 1 criteria provided, single submitter Nov 18, 2013 RCV000790652.1
Likely pathogenic 1 no assertion criteria provided - RCV000510137.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
RB1 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
1110 1195

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Urinary bladder cancer
Retinoblastoma
Small cell lung cancer
Osteosarcoma
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000894012.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Pathogenic
(Nov 18, 2013)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics
Accession: SCV000227619.5
Submitted: (Jun 30, 2017)
Evidence details
Other databases
http://www.egl-eurofins.com/emvc…
Pathogenic
(Mar 30, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000580810.3
Submitted: (Feb 26, 2020)
Evidence details
Publications
PubMed (8)
Comment:
Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Other strong data supporting pathogenic classification
Pathogenic
(Nov 19, 2019)
criteria provided, single submitter
Method: clinical testing
Retinoblastoma
Allele origin: germline
Invitae
Accession: SCV000551831.6
Submitted: (Feb 06, 2020)
Evidence details
Publications
PubMed (15)
Comment:
This sequence change replaces arginine with tryptophan at codon 661 of the RB1 protein (p.Arg661Trp). The arginine residue is highly conserved and there is a … (more)
Pathogenic
(Oct 01, 1999)
no assertion criteria provided
Method: literature only
RETINOBLASTOMA
Allele origin: germline
OMIM
Accession: SCV000034209.1
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (4)
Pathogenic
(Sep 16, 2013)
no assertion criteria provided
Method: research
Retinoblastoma
Allele origin: somatic
Genetic Diagnostic Laboratory,University of Pennsylvania School of Medicine
Accession: SCV000087376.1
Submitted: (Apr 11, 2014)
Evidence details
Likely pathogenic
(-)
no assertion criteria provided
Method: research
Vulvar adenocarcinoma of mammary gland type
(Somatic mutation)
Allele origin: somatic
Genome Sciences Centre,British Columbia Cancer Agency
Accession: SCV000598654.1
Submitted: (Sep 07, 2017)
Evidence details

Citations for this variant

Title Author Journal Year Link
Detection and genomic characterization of a mammary-like adenocarcinoma. Grewal JK Cold Spring Harbor molecular case studies 2017 PMID: 28877932
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
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
A Parent-of-Origin Effect Impacts the Phenotype in Low Penetrance Retinoblastoma Families Segregating the c.1981C>T/p.Arg661Trp Mutation of RB1. Eloy P PLoS genetics 2016 PMID: 26925970
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
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 - - - -

Record last updated Oct 14, 2020