ClinVar Miner

Submissions for variant NM_000321.2(RB1):c.607+1G>T (rs587776789)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492204 SCV000580819 pathogenic Hereditary cancer-predisposing syndrome 2017-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Functionally-validated splicing mutation
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000013969 SCV000493015 pathogenic Retinoblastoma 2014-03-14 criteria provided, single submitter clinical testing
GeneDx RCV000484757 SCV000565875 pathogenic not provided 2016-08-18 criteria provided, single submitter clinical testing This variant is denoted RB1 c.607+1G>T or IVS6+1G>T and consists of a G>T substitution in the -1 position of intron 6 of the RB1 gene. This variant destroys a natural splice donor site and causes abnormal splicing. RNA analyses have demonstrated that RB1 c.607+1G>T causes complete skipping of exon 6, resulting in a premature stop codon in exon 7 (Klutz 2002, Gamez-Pozo 2007). This variant has been reported in multiple individuals with a personal and family history of retinoblastoma (Lohmann 1996, Sutterlin 1999, Alonso 2001, Klutz 2002, Richter 2003, Houdayer 2004,Taylor 2007, Sagi 2015). Multiple segregation analyses have demonstrated reduced penetrance associated with RB1 c.607+1G>T (Klutz 2002, Taylor 2007). Klutz et al. (2002) suggested that paternal inheritance of this variant results in a more penetrant phenotype compared to maternal inheritance. Based on the currently available information, we consider RB1 c.607+1G>T to be pathogenic.
Invitae RCV000013969 SCV000831244 pathogenic Retinoblastoma 2018-06-12 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 6 of the RB1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals and families affected with retinoblastoma (PMID: 8651278, 16269091, 28575107, 17096365). In addition, it has been reported that segregate with the disease with a low penetrance (PMID: 26925970, 12016586). This variant is also known as IVS6+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 13093). Experimental studies have shown that this change causes abnormal splicing which creates a transcript that is lacking of exon 6 and results in a frameshift protein (PMID: 18000883, 12016586). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RB1 are known to be pathogenic (PMID: 17096365). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013969 SCV000034216 pathogenic Retinoblastoma 2002-07-01 no assertion criteria provided literature only

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