Submissions for variant NM_000539.3(RHO):c.541G>A (p.Glu181Lys)

dbSNP: rs775557680

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724301	SCV000228901	pathogenic	not provided	2014-12-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724301	SCV001198576	pathogenic	not provided	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 181 of the RHO protein (p.Glu181Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 1833777, 29068140). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 196282). 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: 8253795, 19913029). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074893	SCV001240497	pathogenic	Retinal dystrophy	2019-08-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000177081	SCV001440598	pathogenic	Retinitis pigmentosa 4	2024-06-28	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PM1,PM2,PP3
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000177081	SCV001443228	pathogenic	Retinitis pigmentosa 4	2020-09-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724301	SCV001962524	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	RHO: PP1:Strong, PM1, PM2, PS4:Moderate, PS3:Supporting
Dept Of Ophthalmology, Nagoya University	RCV001074893	SCV004705660	likely pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074893	SCV005071447	pathogenic	Retinal dystrophy	2020-01-01	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504731	SCV000598752	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000177081	SCV000804694	pathogenic	Retinitis pigmentosa 4	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000504731	SCV000926675	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000504731	SCV001161245	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000724301	SCV001978866	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000724301	SCV001979581	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004755791	SCV005362760	pathogenic	RHO-related disorder	2024-08-22	no assertion criteria provided	clinical testing	The RHO c.541G>A variant is predicted to result in the amino acid substitution p.Glu181Lys. This variant has been reported many times as causative for autosomal dominant retinitis pigmentosa (see for examples: Dryja et al. 1991. PubMed ID: 1833777; Sohocki et al. 2001. PubMed ID: 11139241; Eisenberger et al. 2013. PubMed ID: 24265693: Table S4, Panneman et al. 2023. PubMed ID: 36819107). This variant has not been reported in the large population database gnomAD, indicating this variant is rare. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/196282). Given the evidence, we interpret this variant as pathogenic for autosomal dominant disease.