Submissions for variant NM_000539.3(RHO):c.1021G>A (p.Glu341Lys)

dbSNP: rs142322202

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002602	SCV001160575	uncertain significance	not specified	2019-05-23	criteria provided, single submitter	clinical testing	The RHO c.1021G>A, p.Glu341Lys variant (rs142322202) is reported in the medical literature in at least one individual with autosomal dominant retinitis pigmentosa (Gal 1997, Sullivan 2013). The variant is reported in the general population with an allele frequency of 0.0008% (2/246204 alleles), indicating it is not a common polymorphism. The amino acid at this position is highly conserved but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, the amino acid at this position is thought to be involved in arrestin binding (Rokoczy 2011). Due to limited clinical and functional information, the clinical significance of this variant is uncertain. References: Gal A et al. Rhodopsin Mutations in Inherited Retinal Dystrophies and Dysfunctions. Prog Retin Eye Res 1997 Jan 16(1): 51-79. Rakoczy EP et al. Analysis of Disease-Linked Rhodopsin Mutations Based on Structure, Function, and Protein Stability Calculations. J Mol Biol. 2011 Jan 14;405(2):584-606. Sullivan LS et al. Prevalence of mutations in eyeGENE probands with a diagnosis of autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2013 Sep 19;54(9):6255-61.
Blueprint Genetics	RCV001073614	SCV001239165	likely pathogenic	Retinal dystrophy	2019-07-12	criteria provided, single submitter	clinical testing
Invitae	RCV001213688	SCV001385334	likely pathogenic	not provided	2023-03-10	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RHO function (PMID: 30977563). 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) performed at Invitae indicates that this missense variant is not expected to disrupt RHO protein function. ClinVar contains an entry for this variant (Variation ID: 812033). This missense change has been observed in individuals with clinical features of autosomal dominant retinitis pigmentosa (Invitae). This variant is present in population databases (rs142322202, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 341 of the RHO protein (p.Glu341Lys).
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV001265168	SCV001443255	uncertain significance	Retinitis pigmentosa 4	2020-09-01	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001265168	SCV001573688	uncertain significance	Retinitis pigmentosa 4	2021-04-08	criteria provided, single submitter	research	The RHO c.1021G>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: PM2, PM1. Based on this evidence we have classified this variant as Variant of Uncertain Significance.