ClinVar Miner

Submissions for variant NM_000321.2(RB1):c.1981C>T (p.Arg661Trp) (rs137853294)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492717 SCV000580810 pathogenic Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790652 SCV000227619 pathogenic not provided 2013-11-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763335 SCV000894012 pathogenic Osteosarcoma; Bladder cancer, somatic; Small cell lung cancer; Retinoblastoma 2018-10-31 criteria provided, single submitter clinical testing
Genetic Diagnostic Laboratory,University of Pennsylvania School of Medicine RCV000013962 SCV000087376 pathogenic Retinoblastoma 2013-09-16 no assertion criteria provided research
Genome Sciences Centre,British Columbia Cancer Agency RCV000510137 SCV000598654 likely pathogenic Vulvar adenocarcinoma of mammary gland type no assertion criteria provided research
Invitae RCV000013962 SCV000551831 pathogenic Retinoblastoma 2018-10-21 criteria provided, single submitter clinical testing 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 moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs137853294, ExAC 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). 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). In summary, this variant causes partial loss of function of the RB1 protein and segregates with disease in multiple families, though with reduced penetrance. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013962 SCV000034209 pathogenic Retinoblastoma 1999-10-01 no assertion criteria provided literature only

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