Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000414595 | SCV000491153 | likely pathogenic | not provided | 2016-04-22 | criteria provided, single submitter | clinical testing | The R119P variant in the RPS6KA3 gene has been reported previously in a hemizygous male with Coffin-Lowry syndrome (Delaunoy et al., 2001). The R119P variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R119P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (R114W, T115S, and E118G) have been reported in the Human Gene Mutation Database in association with Coffin-Lowry syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Give the available evidence, the R119P variant is a strong candidate for a pathogenic variant . |
| ARUP Laboratories, |
RCV000414595 | SCV000886059 | likely pathogenic | not provided | 2017-06-23 | criteria provided, single submitter | clinical testing | The p.Arg119Pro variant (rs1057517947) has been previously reported in a male individual included in a cohort of Coffin-Lowry Syndrome (CLS) patients (Delaunoy 2001). This variant is absent from population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser. The arginine at codon 119 is highly conserved considering 12 species up to chicken (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on RPS6KA3 protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). Additionally, a rare variant in an adjacent codon, p.Glu118Gly, has also been reported in a CLS cohort (Delaunoy 2006), suggesting this region of RPS6KA3 is critical for function. Lastly, the p.Arg119Pro variant is listed in the ClinVar database as likely to be pathogenic (Variation ID: 372727). Taken together, we consider the p.Arg119Pro variant to be likely pathogenic. |