ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.1815G>A (p.Met605Ile)

gnomAD frequency: 0.00001  dbSNP: rs1472724809
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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 RCV000804246 SCV000944144 uncertain significance Retinoblastoma 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 605 of the RB1 protein (p.Met605Ile). 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: 649333). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 RCV002406789 SCV002713058 likely benign Hereditary cancer-predisposing syndrome 2023-02-01 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.
All of Us Research Program, National Institutes of Health RCV000804246 SCV004844701 uncertain significance Retinoblastoma 2023-08-25 criteria provided, single submitter clinical testing This missense variant replaces methionine with isoleucine at codon 605 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). Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, RNA or protein functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251092 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.
GeneDx RCV004588266 SCV005080475 uncertain significance not provided 2024-02-05 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; Observed among unaffected controls, but not in any cases in a melanoma study (PMID: 29641532); This variant is associated with the following publications: (PMID: 23516486, 29641532)

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