Submissions for variant NM_000321.3(RB1):c.889A>T (p.Ile297Leu)

dbSNP: rs1286975378

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001953344	SCV002220808	uncertain significance	Retinoblastoma	2022-10-03	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 1443136). This variant has not been reported in the literature in individuals affected with RB1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 297 of the RB1 protein (p.Ile297Leu).
Ambry Genetics	RCV002370585	SCV002685533	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-12	criteria provided, single submitter	clinical testing	The p.I297L variant (also known as c.889A>T), located in coding exon 9 of the RB1 gene, results from an A to T substitution at nucleotide position 889. The isoleucine at codon 297 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003471095	SCV004208498	uncertain significance	Malignant tumor of urinary bladder	2023-10-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001953344	SCV004844635	uncertain significance	Retinoblastoma	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 297 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). 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.