Submissions for variant NM_000321.3(RB1):c.509A>G (p.Glu170Gly)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002579704	SCV002938763	uncertain significance	Retinoblastoma	2022-04-21	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with RB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 170 of the RB1 protein (p.Glu170Gly).
All of Us Research Program, National Institutes of Health	RCV002579704	SCV004844610	uncertain significance	Retinoblastoma	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 170 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 hereditary cancer 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.
Ambry Genetics	RCV004064346	SCV005034503	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-11	criteria provided, single submitter	clinical testing	The p.E170G variant (also known as c.509A>G), located in coding exon 5 of the RB1 gene, results from an A to G substitution at nucleotide position 509. The glutamic acid at codon 170 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.