Submissions for variant NM_000539.3(RHO):c.1040C>T (p.Pro347Leu)

gnomAD frequency: 0.00001  dbSNP: rs29001566

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490027	SCV000577308	pathogenic	not provided	2022-10-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with partial delocalization of rhodopsin proteins to the lateral plasma membrane, Golgi apparatus, and synaptic terminal (Tam et al., 2000); Missense variants in the same residue (P347T, P347S, P347A, P347Q, P347R) reported in the Human Gene Mutation Database in individuals with retinitis pigmentosa (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9538889, 33629268, 32531858, 18385078, 34758253, 20555336, 25221422, 22217031, 18175313, 9335046, 2215617, 21094163, 26667666, 26202387, 28559085, 30972525, 30977563, 31054281, 31960602, 11139241, 32581362, 31630094, 33851411, 19074802, 31206141, 2021172, 33576794, 33090715, 33946315, 35656873, 11134067)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626702	SCV000747405	pathogenic	Blurred vision; Night blindness; Peripheral visual field loss	2017-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000490027	SCV001203323	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 347 of the RHO protein (p.Pro347Leu). This variant is present in population databases (rs29001566, gnomAD 0.0008%). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 2215617, 25221422). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13014). 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 expected to disrupt RHO protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075874	SCV001241515	pathogenic	Retinal dystrophy	2019-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000490027	SCV001246343	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	RHO: PP1:Strong, PM1, PM2, PM5, PP4, PS4:Supporting
Institute of Human Genetics, University of Leipzig Medical Center	RCV000013888	SCV001440597	likely pathogenic	Retinitis pigmentosa 4	2019-01-01	criteria provided, single submitter	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000013888	SCV001443259	pathogenic	Retinitis pigmentosa 4	2020-09-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000490027	SCV001447284	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000013888	SCV001573641	pathogenic	Retinitis pigmentosa 4	2021-04-08	criteria provided, single submitter	research	The RHO c.1040C>T 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, PM5, PS3, PP1-M. Based on this evidence we have classified this variant as Pathogenic.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV000504743	SCV004030290	pathogenic	Retinitis pigmentosa	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Dept Of Ophthalmology, Nagoya University	RCV001075874	SCV004705682	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
OMIM	RCV000013888	SCV000034135	pathogenic	Retinitis pigmentosa 4	2010-09-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504743	SCV000598749	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV000013888	SCV001760108	pathogenic	Retinitis pigmentosa 4		no assertion criteria provided	clinical testing