ClinVar Miner

Submissions for variant NM_000321.2(RB1):c.1814T>C (p.Met605Thr) (rs1555293654)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000529955 SCV000629294 uncertain significance Retinoblastoma 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 605 of the RB1 protein (p.Met605Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant also falls at the last nucleotide of exon 18 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) and has not been reported in the literature in individuals with an RB1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098) but according to multiple splice site algorithms this particular variant is not predicted to significantly affect splicing. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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