ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.1991C>T (p.Thr664Ile)

dbSNP: rs749739772
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001241114 SCV001414109 uncertain significance Retinoblastoma 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 664 of the RB1 protein (p.Thr664Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RB1-related conditions. This variant is not present in population databases (ExAC no frequency).
Ambry Genetics RCV002418827 SCV002718571 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-25 criteria provided, single submitter clinical testing The p.T664I variant (also known as c.1991C>T), located in coding exon 20 of the RB1 gene, results from a C to T substitution at nucleotide position 1991. The threonine at codon 664 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV001241114 SCV004835461 uncertain significance Retinoblastoma 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 664 of the RB1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RB1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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