ClinVar Genomic variation as it relates to human health

The RHO c.50C>T; p.Thr17Met variant (rs104893769) is reported in the medical literature as segregating with disease in families with retinitis pigemtosa (Jacobson 2016, Sheffield 1991, Sung 1991). Additionally, functional studies of this variant in cell culture and in a mouse model show the rhodopsin protein is deficient (Krebs 2010, Li 1998). This variant is reported in the ClinVar database (Variation ID: 13018) and in the Genome Aggregation Database in 1 out of 30948 alleles, indicating it is not a common polymorphism. The threonine at codon 17 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Additionally, other variants in this region are considered pathogenic (see link to RHO variants in ClinVar below). Considering available information, this variant is classified as pathogenic. Pathogenic RHO variants are causative for autosomal dominant or recessive retinitis pigmentosa (MIM: 613731) or retinitis punctata albescens (MIM: 136880). However, this variant is specifically associated with autosomal dominant retinitis pigmentosa. References: Link to RHO variants in ClinVar: http://www.ncbi.nlm.nih.gov/clinvar/?term=RHO%5Bgene%5D Jacobson SG et al. Complexity of the Class B Phenotype in Autosomal Dominant Retinitis Pigmentosa Due to Rhodopsin Mutations. Invest Ophthalmol Vis Sci. 2016 Sep 1;57(11):4847-4858. Krebs MP et al. Molecular mechanisms of rhodopsin retinitis pigmentosa and the efficacy of pharmacological rescue. J Mol Biol. 2010 Feb 5;395(5):1063-78. Li T et al. Effect of vitamin A supplementation on rhodopsin mutants threonine-17 --> methionine and proline-347 --> serine in transgenic mice and in cell cultures. Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11933-8. Sheffield VC et al. Identification of novel rhodopsin mutations associated with retinitis pigmentosa by GC-clamped denaturing gradient gel electrophoresis. Am J Hum Genet. 1991 Oct;49(4):699-706. Sung CH et al. Rhodopsin mutations in autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6481-5.

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 17 of the RHO protein (p.Thr17Met). This variant is present in population databases (rs104893769, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 1897520, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13018). Advanced 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 at Invitae 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 RHO protein function. Experimental studies have shown that this missense change affects RHO function (PMID: 19913029). For these reasons, this variant has been classified as Pathogenic.

RHO: PP1:Strong, PM2, PS3:Moderate, PS4:Moderate