Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492301 | SCV000580765 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2015-10-30 | criteria provided, single submitter | clinical testing | The c.380G>C variant (also known as p.S127T), located in coding exon 3 of the RB1 gene, results from a G to C substitution at nucleotide position 380. The amino acid change results in serine to threonine at codon 127, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. <span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px">Using two different splice site prediction tools, BDGP and ESE,this alteration is predicted to cause a decrease in the native donor splice site strength but does not abolish it.One study reported the p.S127T variant as causing a loss of the donor splice site (VanOrsouw<span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px">et al. Hum.Mol.Genet.1996;5(6): 755-61).This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage of 6502 at this position. This nucleotide and amino acid position is highlyconserved on sequence alignment.In addition, this alteration is predicted to be tolerated by in silico analysis.<span style="background-color:rgb(255, 255, 255); color:rgb(51, 51, 51); font-family:sans-serif,arial,verdana,trebuchet ms; font-size:13px">Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV000814584 | SCV000954997 | likely pathogenic | Retinoblastoma | 2021-12-11 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser127 amino acid residue in RB1. Other variant(s) that disrupt this residue have been observed in individuals with RB1-related conditions (PMID: 15884040), which suggests that this may be a clinically significant amino acid residue. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 428661). This missense change has been observed in individuals with bilateral retinoblastoma (PMID: 8776589, 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 127 of the RB1 protein (p.Ser127Thr). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. |