Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492155 | SCV000580796 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2015-08-05 | criteria provided, single submitter | clinical testing | ​The p.D286G variant (also known as c.857A>G) is located in coding exon 8 of the RB1 gene. This alteration results from an A to G substitution at nucleotide position 857. The aspartic acid at codon 286 is replaced by glycine, an amino acid with similar properties. This alteration has been detected in a 12-year-old Brazilian female with bilateral retinoblastoma and also a 3-year-old female with bilateral retinoblastoma (Barbosa RH et al. Invest Ophthalmol Vis Sci. 2013 May 7;54(5):3184-94; Dommering CJ et al. Fertil. Steril. 2012 Jan;97(1):79-81). This variant co-segregated with disease in 3 individuals from one family tested in our laboratory (Ambry internal data). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, <span style="font-family:arial,sans-serif; font-size:10pt">the <span style="font-family:arial,sans-serif">in silico prediction for this alteration is inconclusive. Using the HSF and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV000684899 | SCV000812360 | pathogenic | Retinoblastoma | 2024-12-23 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 286 of the RB1 protein (p.Asp286Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinoblastoma (PMID: 23532519; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 428682). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RB1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Genetic Diagnostic Laboratory, |
RCV000684899 | SCV005046036 | likely pathogenic | Retinoblastoma | 2024-05-20 | criteria provided, single submitter | clinical testing | Case and Pedigree Information: BILATERAL CASES:1, UNILATERAL CASES:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:PM2 |