Submissions for variant NM_000539.3(RHO):c.50C>T (p.Thr17Met)

gnomAD frequency: 0.00001  dbSNP: rs104893769

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002098	SCV001159945	pathogenic	not specified	2018-09-27	criteria provided, single submitter	clinical testing	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.
Blueprint Genetics	RCV001075619	SCV001241246	pathogenic	Retinal dystrophy	2019-02-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001090660	SCV001246333	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	RHO: PP1:Strong, PM2, PS3:Moderate, PS4:Moderate
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000013892	SCV001443197	pathogenic	Retinitis pigmentosa 4	2020-09-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001090660	SCV001480138	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001090660	SCV001583958	pathogenic	not provided	2024-12-08	criteria provided, single submitter	clinical testing	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). 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 RHO protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RHO function (PMID: 19913029). For these reasons, this variant has been classified as Pathogenic.
Dept Of Ophthalmology, Nagoya University	RCV001075619	SCV004705635	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075619	SCV005069384	pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
SingHealth Duke-NUS Institute of Precision Medicine	RCV000013892	SCV005881663	pathogenic	Retinitis pigmentosa 4	2025-02-05	criteria provided, single submitter	clinical testing	Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1). Other variant at this amino acid residue has been classified as pathogenic (PM5, p.Thr17Lys). Prevalence of variant is increased in affected patients compared to the general population (PS4). Experimental studies have shown that this missense change affects RHO function (PS3, PMID: 19913029).
OMIM	RCV000013892	SCV000034139	pathogenic	Retinitis pigmentosa 4	1991-09-15	no assertion criteria provided	literature only
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787682	SCV000926673	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research