ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.1223C>T (p.Thr408Ile)

gnomAD frequency: 0.00001  dbSNP: rs1462238834
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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 RCV000796634 SCV000936155 uncertain significance Retinoblastoma 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 408 of the RB1 protein (p.Thr408Ile). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 643031). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RB1 protein function. 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.
Ambry Genetics RCV002360926 SCV002656563 uncertain significance Hereditary cancer-predisposing syndrome 2024-08-31 criteria provided, single submitter clinical testing The p.T408I variant (also known as c.1223C>T), located in coding exon 13 of the RB1 gene, results from a C to T substitution at nucleotide position 1223. The threonine at codon 408 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. 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 RCV000796634 SCV005430216 uncertain significance Retinoblastoma 2024-07-10 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 408 of the RB1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 been identified in 1/250962 chromosomes 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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