Submissions for variant NM_000539.3(RHO):c.68C>A (p.Pro23His)

dbSNP: rs104893768

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490234	SCV000576880	pathogenic	not provided	2022-11-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with impaired function and decreased thermal stability of the RHO protein as well as increased photoreceptor cell death (Noorwez et al., 2004; Comitato et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19913029, 24853414, 21372525, 24515108, 19933196, 22110080, 24618321, 20164459, 21094163, 23185477, 8643442, 16799052, 29890221, 26427410, 34666717, 30977563, 18385078, 31717845, 20805032, 24214395, 22323724, 24106275, 21224384, 22276148, 27149983, 27654411, 26202387, 2137202, 28559085, 31100078, 31908405, 11139241, 2239971, 32037395, 14769795)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000490234	SCV000884459	pathogenic	not provided	2017-12-05	criteria provided, single submitter	clinical testing	The RHO c.68C>A; p.Pro23His variant (rs104893768) is published in the medical literature in individuals and families with autosomal dominant retinitis pigmentosa (RP; Bonilha 2015, Dryja 1990, Jacobson 2016). Additionally, other variants in this codon, p.Pro23Ala and p.Pro23Leu are described in individuals and families with autosomal dominant RP (Dryja 1991, Oh 2000). The c.68C>A; p.Pro23His variant is listed in the ClinVar database (Variation ID: 13013), but not in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at this position is well conserved across species and computational algorithms (PolyPhen-2, SIFT) predict the p.Pro23His variant is deleterious. Additionally, functional studies in a mouse model show this variant causes altered function (Comitato 2016). Considering available information, this variant is classified as pathogenic. Pathogenic RHO variants are causative for autosomal dominant or recessive retinitis pigmentosa (MIM#613731). References: Bonilha VL et al. Retinal histopathology in eyes from patients with autosomal dominant retinitis pigmentosa caused by rhodopsin mutations. Graefes Arch Clin Exp Ophthalmol. 2015 Dec;253(12):2161-9. Comitato A et al. Dominant and recessive mutations in rhodopsin activate different cell death pathways. Hum Mol Genet. 2016 Jul 1;25(13):2801-2812. Dryja TP et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature. 1990 Jan 25;343(6256):364-6. Dryja TP et al. Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis pigmentosa. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9370-4. 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. Oh KT et al. Description of a new mutation in rhodopsin, Pro23Ala, and comparison with electroretinographic and clinical characteristics of the Pro23His mutation. Arch Ophthalmol. 2000 Sep;118(9):1269-76.
Fulgent Genetics, Fulgent Genetics	RCV000763095	SCV000893632	pathogenic	Congenital stationary night blindness autosomal dominant 1; Pigmentary retinal dystrophy; Retinitis pigmentosa 4	2022-01-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000490234	SCV001205315	pathogenic	not provided	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 23 of the RHO protein (p.Pro23His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 1987956, 2137202, 11879142, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13013). 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: 1418997, 19913029, 22323724, 24853414). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075876	SCV001241517	pathogenic	Retinal dystrophy	2019-08-15	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000013887	SCV001573281	pathogenic	Retinitis pigmentosa 4	2021-04-08	criteria provided, single submitter	research	The RHO c.68C>A variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic.
OMIM	RCV000013887	SCV000034134	pathogenic	Retinitis pigmentosa 4	2005-01-14	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004755731	SCV005345275	pathogenic	RHO-related disorder	2024-09-25	no assertion criteria provided	clinical testing	The RHO c.68C>A variant is predicted to result in the amino acid substitution p.Pro23His. This variant has been reported as a recurrent causative variant for autosomal dominant retinitis pigmentosa (see for examples Dryja et al. 1990. PubMed ID: 2137202; Sohocki et al. 2001. PubMed ID: 11139241; Coussa et al. 2019. PubMed ID: 31908405). Patients with this variant have been reported to exhibit interfamilial and intrafamilial phenotypic variability (Berson et al. 1991. PubMed ID: 1987956). Several functional studies have shown that the p.Pro23His substitution decreases both protein stability and activity (see for example Krebs et al. 2010. PubMed ID: 19913029). This variant has not been reported in the large population database gnomAD, indicating this variant is rare. Given the evidence, we interpret this variant as pathogenic for autosomal dominant disease.