Submissions for variant NM_000322.5(PRPH2):c.422A>G (p.Tyr141Cys)

dbSNP: rs61755781

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000084969	SCV000708640	pathogenic	not provided	2017-05-22	criteria provided, single submitter	clinical testing
Invitae	RCV001051727	SCV001215897	pathogenic	PRPH2-related disorder	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 141 of the PRPH2 protein (p.Tyr141Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa or pattern dystrophy (PMID: 16113362, 16799052, 25082885, 25097241). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98666). 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 PRPH2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PRPH2 function (PMID: 25001182). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074856	SCV001240457	pathogenic	Retinal dystrophy	2019-07-31	criteria provided, single submitter	clinical testing
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250306	SCV001424619	pathogenic	Stargardt disease	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.422A>G in the PRPH2 gene has been previously studied (PMIDs 11139241,15370544, 22466463, 25082885, 25001182, 25097241, 28559085). We found this variant in 14 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755781,CM010125). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS3, PS4, PM1, PM2, PP3, PP5, PP1-S] and classified NM_000322.4:c.422A>G in the PRPH2 gene as a Pathogenic mutation.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250316	SCV001424636	pathogenic	Patterned dystrophy of the retinal pigment epithelium	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.422A>G in the PRPH2 gene has been previously studied (PMIDs 11139241, 15370544, 22466463, 25082885, 25001182, 25097241, 28559085). We found this variant in 14 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755781,CM010125). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS3, PS4, PM1, PM2, PP3, PP5, PP1-S] and classified NM_000322.4:c.422A>G in the PRPH2 gene as a Pathogenic mutation.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250317	SCV001424637	pathogenic	Cone-rod dystrophy	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.422A>G in the PRPH2 gene has been previously studied (PMIDs 11139241, 15370544, 22466463, 25082885, 25001182, 25097241, 28559085). We found this variant in 14 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755781,CM010125). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS3, PS4, PM1, PM2, PP3, PP5, PP1-S] and classified NM_000322.4:c.422A>G in the PRPH2 gene as a Pathogenic mutation.
Institute of Medical Molecular Genetics, University of Zurich	RCV001353037	SCV001548153	likely pathogenic	Autosomal recessive bestrophinopathy	2021-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000084969	SCV001804289	pathogenic	not provided	2020-11-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (alteration of PRPH2 protein complex formation) (Stuck et al., 2014); 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: 32531846, 28559085, 29961824, 28053051, 15370544, 12882809, 11139241, 25082885, 25097241, 22466463, 25001182)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723663	SCV001950344	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Tyr141Cys variant in PRPH2 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PP1, PS4. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Retina International	RCV000084969	SCV000117105	not provided	not provided		no assertion provided	not provided
OMIM	RCV002508140	SCV000211870	pathogenic	Vitelliform macular dystrophy 3	2014-12-01	no assertion criteria provided	literature only
OMIM	RCV000161145	SCV000211871	pathogenic	Patterned macular dystrophy 1	2014-12-01	no assertion criteria provided	literature only
Leiden Open Variation Database	RCV000084969	SCV001745048	pathogenic	not provided	2021-06-25	no assertion criteria provided	curation	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Julia Lopez, LOVD, Manon Peeters.