Submissions for variant NM_000322.5(PRPH2):c.658C>T (p.Arg220Trp)

dbSNP: rs61755809

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001075102	SCV001240713	likely pathogenic	Retinal dystrophy	2018-08-02	criteria provided, single submitter	clinical testing
Invitae	RCV001247286	SCV001420698	pathogenic	PRPH2-related disorder	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 220 of the PRPH2 protein (p.Arg220Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinal dystrophy (PMID: 9443872, 16916875, 17653047, 29555955). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98698). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRPH2 protein function. For these reasons, this variant has been classified as Pathogenic.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250379	SCV001424715	uncertain significance	Patterned dystrophy of the retinal pigment epithelium	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.658C>T in the PRPH2 gene has been previously studied(PMIDs 9443872, 26796962, 29555955, 29453956). We found this variant in 1 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755809,CM984094). It is absent in gnomAD browser. It is not enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PM1, PM2, PP3] and classified NM_000322.4:c.658C>T in the PRPH2 gene as a Variant of Uncertain Significance.
GeneDx	RCV000085010	SCV001818281	likely pathogenic	not provided	2021-04-13	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); 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: 33090715, 30718709, 29555955, 17653047, 26796962, 29453956, 16916875, 9443872)
MGZ Medical Genetics Center	RCV002288583	SCV002579026	likely pathogenic	Vitelliform macular dystrophy 3	2022-03-23	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001075102	SCV004707335	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Retina International	RCV000085010	SCV000117146	not provided	not provided		no assertion provided	not provided
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787873	SCV000926889	uncertain significance	Macular dystrophy	2018-04-01	no assertion criteria provided	research
Leiden Open Variation Database	RCV000085010	SCV001744988	pathogenic	not provided	2021-04-06	no assertion criteria provided	curation	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: LOVD, Manon Peeters, Yoshito Koyanagi.