ClinVar Miner

Submissions for variant NM_000321.2(RB1):c.1399C>T (p.Arg467Ter) (rs398123331)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492734 SCV000580830 pathogenic Hereditary cancer-predisposing syndrome 2018-04-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078633 SCV000226220 pathogenic not provided 2013-03-13 criteria provided, single submitter clinical testing
GeneDx RCV000078633 SCV000617262 pathogenic not provided 2017-05-15 criteria provided, single submitter clinical testing This pathogenic variant is denoted RB1 c.1399C>T at the cDNA level and p.Arg467Ter (R467X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in several individuals with bilateral retinoblastoma and is considered pathogenic (Blanquet 1995, Richter 2003, Brichard 2006, Saliminejad 2013, Dommering 2014, Devarajan 2015, Grotta 2015).
Genetic Diagnostic Laboratory,University of Pennsylvania School of Medicine RCV000114730 SCV000087354 pathogenic Retinoblastoma 2013-09-16 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000492734 SCV000696562 pathogenic Hereditary cancer-predisposing syndrome 2017-01-24 criteria provided, single submitter clinical testing Variant summary: The RB1 c.1399C>T (p.Arg467X) variant results in a premature termination codon, predicted to cause a truncated or absent RB1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. If this variant escapes NMD, it is expected to truncate Retinoblastoma-associated protein, A-box, Retinoblastoma-associated protein, B-box and Retinoblastoma-associated protein, C-terminal (via InterPro). Truncations downstream of this position have been classified as pathogenic clinical laboratories in ClinVar (e.g. p.Gln504Ter, p.Trp563Ter, p.Gln850Ter, etc). This variant is absent in 24658 control chromosomes from ExAC. In literature, this variant is reported as a recurrent pathogenic variant that causes retinoblastoma. The variant is found as germline as well as somatic variant in retinoblastoma patients. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000114730 SCV000551832 pathogenic Retinoblastoma 2018-10-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 467 (p.Arg467*) of 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. This particular variant has been reported in the literature in many individuals affected with retinoblastoma (PMID: 7795591, 25928201, 25928201, 24688104, 26530098). For these reasons, this variant has been classified as Pathogenic.

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