ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.1163T>G (p.Ile388Ser)

gnomAD frequency: 0.00001  dbSNP: rs373623059
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000823567 SCV000964429 uncertain significance Retinoblastoma 2023-11-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 388 of the RB1 protein (p.Ile388Ser). This variant is present in population databases (rs373623059, gnomAD 0.003%). 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: 665312). 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) performed at Invitae indicates that this missense variant is not expected to disrupt RB1 protein function with a negative predictive value of 80%. 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 RCV002319924 SCV002626497 likely benign Hereditary cancer-predisposing syndrome 2023-03-09 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV003128716 SCV003805704 uncertain significance not provided 2022-08-18 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Dayalan_2006_Review)
Baylor Genetics RCV003467519 SCV004208530 uncertain significance Malignant tumor of urinary bladder 2023-07-19 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000823567 SCV004822853 uncertain significance Retinoblastoma 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with serine at codon 388 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 3/250752 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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