Submissions for variant NM_000322.5(PRPH2):c.659G>A (p.Arg220Gln)

gnomAD frequency: 0.00001  dbSNP: rs61755810

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001075618	SCV001241245	likely pathogenic	Retinal dystrophy	2019-02-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001346727	SCV001540952	pathogenic	PRPH2-related disorder	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 220 of the PRPH2 protein (p.Arg220Gln). This variant is present in population databases (rs61755810, gnomAD 0.004%). This missense change has been observed in individuals with PRPH2-related conditions (PMID: 8994365, 30822235). ClinVar contains an entry for this variant (Variation ID: 98699). 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 PRPH2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PRPH2 function (PMID: 26796962). This variant disrupts the p.Arg220 amino acid residue in PRPH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9443872, 16916875, 17653047; 29555955.). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000085011	SCV001765310	likely pathogenic	not provided	2025-03-21	criteria provided, single submitter	clinical testing	Identified in patients with PRPH2-related eye disorders referred for genetic testing at GeneDx and in published literature (PMID: 24629188, 8956033, 8994365); Observed in homozygous state in a patient in published literature with pediatric-onset cone-rod dystrophy and not observed in homozygous state in controls. Heterozygous parents had macular abnormalities. (PMID: 30822235); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34411390, 34240658, 8956033, 8675410, 31456290, 36393903, 38743414, 26796962, 8994365, 24629188, 30822235, 36648066)
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075618	SCV005070605	pathogenic	Retinal dystrophy	2017-01-01	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798773	SCV005420776	pathogenic	Macular dystrophy	2024-10-04	criteria provided, single submitter	research	PS3,PS4,PM2,PM5,PP3,PM1
Retina International	RCV000085011	SCV000117147	not provided	not provided		no assertion provided	not provided
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003141	SCV001161210	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Leiden Open Variation Database	RCV000085011	SCV001744990	pathogenic	not provided	2021-04-06	no assertion criteria provided	curation	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Global Variome, with Curator vacancy, LOVD, Manon Peeters.