Submissions for variant NM_000539.3(RHO):c.448G>A (p.Glu150Lys)

dbSNP: rs104893791

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045970	SCV001209847	pathogenic	not provided	2024-09-21	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 150 of the RHO protein (p.Glu150Lys). This variant is present in population databases (rs104893791, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive retinitis pigmentosa (PMID: 19960070, 26887858). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13046). 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 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: 23221340). For these reasons, this variant has been classified as Pathogenic.
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV001265186	SCV001443218	likely pathogenic	Retinitis pigmentosa 4	2020-09-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004794339	SCV005068397	likely pathogenic	Retinal dystrophy	2020-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001265186	SCV005398880	pathogenic	Retinitis pigmentosa 4	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital stationary night blindness (MIM#610445), retinitis pigmentosa 4 (MIM#613731) and retinitis punctata albescens (MIM#136880). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Variants associated with dominant conditions in this gene are known to have variable expressivity and age of onset (PMID: 26887858). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (12 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated 7 transmembrane receptor (rhodopsin family) domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been pathogenic or likely pathogenic by clinical laboratories in ClinVar, and has been observed as homozygous in four unrelated families in the literature all with retinitis pigmentosa (PMID: 19960070, 26887858, 37165311). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregates with disease in a large family retinitis pigmentosa (PMID: 19960070). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Knock-in mice homozygous for this variant displayed rapid retinal degeneration (PMID: 23221340). (SP) 1207 - Parental origin of the variant is unresolved (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV004794339	SCV005415419	pathogenic	Retinal dystrophy	2024-05-27	criteria provided, single submitter	research
OMIM	RCV000013921	SCV000034168	pathogenic	Retinitis pigmentosa 4, autosomal recessive	2006-08-04	no assertion criteria provided	literature only
Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology	RCV003105773	SCV002600104	pathogenic	Autosomal recessive retinitis pigmentosa	2022-08-22	no assertion criteria provided	research