Submissions for variant NM_000321.3(RB1):c.2093G>C (p.Arg698Thr)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002424072	SCV002725802	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	clinical testing	The p.R698T variant (also known as c.2093G>C), located in coding exon 20 of the RB1 gene, results from a G to C substitution at nucleotide position 2093. The arginine at codon 698 is replaced by threonine, an amino acid with similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with RB1-related disease (Ambry internal data). Based on internal structural analysis, R698T is deleterious. The variant is mildly destabilizing to the local structure. The variant has nearby pathogenic variants and has no nearby benign variants. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003098609	SCV003210620	uncertain significance	Retinoblastoma	2024-08-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 698 of the RB1 protein (p.Arg698Thr). This variant is not present in population databases (gnomAD no frequency). 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: 1785760). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RB1 protein function with a positive predictive value of 80%. 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.
Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine	RCV003098609	SCV005046260	likely pathogenic	Retinoblastoma	2024-05-20	criteria provided, single submitter	clinical testing	Case and Pedigree Information: BILATERAL CASES:0, UNILATERAL CASES:3, TOTAL CASES:3, PEDIGREES:2. ACMG Codes Applied:PM1, PM2, PS4SUP