ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.1981C>T (p.Arg661Trp)

gnomAD frequency: 0.00002  dbSNP: rs137853294
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine RCV000013962 SCV000087376 pathogenic Retinoblastoma 2024-05-20 criteria provided, single submitter clinical testing Case and Pedigree Information: BILATERAL CASES:5, UNILATERAL CASES:7, TOTAL CASES:12, PEDIGREES:12. ACMG Codes Applied:PM2, PS4M
Eurofins Ntd Llc (ga) RCV000790652 SCV000227619 pathogenic not provided 2013-11-18 criteria provided, single submitter clinical testing
Invitae RCV000013962 SCV000551831 pathogenic Retinoblastoma 2023-09-30 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000492717 SCV000580810 pathogenic Hereditary cancer-predisposing syndrome 2022-07-21 criteria provided, single submitter clinical testing 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.
Fulgent Genetics, Fulgent Genetics RCV000763335 SCV000894012 pathogenic Bone osteosarcoma; Malignant tumor of urinary bladder; Small cell lung carcinoma; Retinoblastoma 2018-10-31 criteria provided, single submitter clinical testing
Department of Pediatrics, Memorial Sloan Kettering Cancer Center RCV000013962 SCV001478170 pathogenic Retinoblastoma 2020-12-15 criteria provided, single submitter research
Genetics and Molecular Pathology, SA Pathology RCV000013962 SCV002556662 pathogenic Retinoblastoma 2019-07-24 criteria provided, single submitter clinical testing 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.
GeneDx RCV000790652 SCV003194892 pathogenic not provided 2023-01-23 criteria provided, single submitter clinical testing 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)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000013962 SCV004171512 pathogenic Retinoblastoma 2023-10-25 criteria provided, single submitter clinical testing The RB1 c.1981C>T (p.Arg661Trp) missense change has a maximum non-founder subpopulation frequency of 0.0060% in gnomAD v2.1.1 ( 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.
OMIM RCV000013962 SCV000034209 pathogenic Retinoblastoma 1999-10-01 no assertion criteria provided literature only
Genome Sciences Centre, British Columbia Cancer Agency RCV000510137 SCV000598654 likely pathogenic Vulvar adenocarcinoma of mammary gland type no assertion criteria provided research
GenomeConnect, ClinGen RCV000013962 SCV002075237 not provided Retinoblastoma no assertion provided phenotyping only 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.

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