Submissions for variant NM_000321.3(RB1):c.2504T>C (p.Ile835Thr)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002455633	SCV002738824	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-06	criteria provided, single submitter	clinical testing	The p.I835T variant (also known as c.2504T>C), located in coding exon 24 of the RB1 gene, results from a T to C substitution at nucleotide position 2504. The isoleucine at codon 835 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly 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.
GeneDx	RCV002464664	SCV002759076	uncertain significance	not provided	2022-06-01	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: 23516486)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003101901	SCV003231324	uncertain significance	Retinoblastoma	2022-05-17	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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is present in population databases (rs776167810, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 835 of the RB1 protein (p.Ile835Thr).
All of Us Research Program, National Institutes of Health	RCV003101901	SCV004832406	uncertain significance	Retinoblastoma	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 835 of the RB1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 1/250632 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.