ClinVar Miner

Submissions for variant NM_000321.2(RB1):c.380G>C (p.Ser127Thr) (rs1131690843)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492301 SCV000580765 likely pathogenic Hereditary cancer-predisposing syndrome 2015-10-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
Invitae RCV000814584 SCV000954997 likely pathogenic Retinoblastoma 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 127 of the RB1 protein (p.Ser127Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant also falls at the last nucleotide of exon 3 of the RB1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with bilateral retinoblastoma in the literature (PMID: 8776589) and in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 428661). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the 127 amino acid residue in RB1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15884040), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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