ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.1750G>T (p.Asp584Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1343212063
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001057017 SCV001221486 uncertain significance Retinoblastoma 2022-08-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 584 of the RB1 protein (p.Asp584Tyr). 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: 852418). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 RCV002400325 SCV002711647 uncertain significance Hereditary cancer-predisposing syndrome 2022-07-11 criteria provided, single submitter clinical testing The p.D584Y variant (also known as c.1750G>T), located in coding exon 18 of the RB1 gene, results from a G to T substitution at nucleotide position 1750. The aspartic acid at codon 584 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. 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.
Baylor Genetics RCV003462566 SCV004208536 uncertain significance Malignant tumor of urinary bladder 2023-06-23 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV001057017 SCV004844695 uncertain significance Retinoblastoma 2023-11-30 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with tyrosine at codon 584 of the RB1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 1/250988 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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