Submissions for variant NM_000539.3(RHO):c.563G>A (p.Gly188Glu)

dbSNP: rs1424131846

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001281	SCV001158457	likely pathogenic	not specified	2019-06-03	criteria provided, single submitter	clinical testing	The RHO c.563G>A, p.Gly188Glu variant (rs1424131846) is reported in the medical literature in individuals and families with autosomal dominant retinitis pigmentosa (Macke 2014, Van Cauwenbergh 2017) and reportedly occurs de novo in one individual (Stone 2017). Additionally, another variant in the same codon, c.562G>A; p.Gly188Arg, is reported in several additional families with autosomal dominant retinitis pigmentosa (Dryja 1991, Martin-Merida 2018, Wang 2014) and displays altered functional properties including improper cellular localization and oligomerization (Gragg 2018). The c.563G>A, p.Gly188Glu variant is reported in the general population with an overall allele frequency of 0.0004% (1/246228 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The amino acid at this position is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. References: Gragg M and Park PS. Misfolded rhodopsin mutants display variable aggregation properties. Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt B):2938-2948 Macke JP et al. Identification of novel rhodopsin mutations responsible for retinitis pigmentosa: implications for the structure and function of rhodopsin. Am J Hum Genet. 1993 Jul;53(1):80-9. Martin-Merida I et al. Toward the Mutational Landscape of Autosomal Dominant Retinitis Pigmentosa: A Comprehensive Analysis of 258 Spanish Families. Invest Ophthalmol Vis Sci. 2018 May 1;59(6):2345-2354. Stone EM et al. Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology. 2017 Sep;124(9):1314-1331. Van Cauwenbergh C et al. Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families. PLoS One. 2017 Jan 11;12(1):e0170038.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001041691	SCV001205320	pathogenic	not provided	2024-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 188 of the RHO protein (p.Gly188Glu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 8317502, 28076437, 28559085). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 811432). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RHO function (PMID: 8253795). For these reasons, this variant has been classified as Pathogenic.
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV001265198	SCV001443234	likely pathogenic	Retinitis pigmentosa 4	2020-09-01	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV001265198	SCV002521595	pathogenic	Retinitis pigmentosa 4	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 8253795). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.71; 3Cnet: 0.79). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000811432). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 28076437 ,28559085 ,8317502). A different missense change at the same codon (p.Gly188Arg) has been reported to be associated with RHO related disorder (ClinVar ID: VCV000143081 / PMID: 1833777). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences	RCV004756151	SCV005361780	pathogenic	RHO-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The RHO c.563G>A variant is predicted to result in the amino acid substitution p.Gly188Glu. This recurrent variant has been reported in individuals with autosomal dominant retinitis pigmentosa (Macke et al. 1993. PubMed ID: 8317502; Cauwenbergh et al. 2017. PubMed ID: 28076437; Supplemental Table 7; Panneman et al. 2023. PubMed ID: 36819107; Table S1, Lin et al. 2024. PubMed ID: 38219857). Functional studies suggested that this variant resulted in retention of the protein at the endoplasmic reticulum and cannot easily reconstitute with 11-cis-retinal (Rakoczy et al. 2011. PubMed ID: 21094163). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.