ClinVar Miner

Submissions for variant NM_000321.3(RB1):c.2198A>T (p.His733Leu)

gnomAD frequency: 0.00001  dbSNP: rs778503152
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001014746 SCV001175495 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-11 criteria provided, single submitter clinical testing The p.H733L variant (also known as c.2198A>T), located in coding exon 21 of the RB1 gene, results from an A to T substitution at nucleotide position 2198. The histidine at codon 733 is replaced by leucine, 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001306596 SCV001495976 likely benign Retinoblastoma 2025-01-08 criteria provided, single submitter clinical testing
GeneDx RCV003442144 SCV004167686 uncertain significance not provided 2023-04-19 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Day alan_2006_Review)
All of Us Research Program, National Institutes of Health RCV001306596 SCV004844726 uncertain significance Retinoblastoma 2023-08-08 criteria provided, single submitter clinical testing This missense variant replaces histidine with leucine at codon 733 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 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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