Submissions for variant NM_000322.5(PRPH2):c.514C>T (p.Arg172Trp)

dbSNP: rs61755792

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049315	SCV001213360	pathogenic	PRPH2-related disorder	2025-01-18	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 172 of the PRPH2 protein (p.Arg172Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant macular dystrophy (PMID: 8485576, 8747448). It has also been observed to segregate with disease in related individuals. This variant is also known as RDS p.Arg172Trp. ClinVar contains an entry for this variant (Variation ID: 13170). 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: 24463884). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000084981	SCV001246205	pathogenic	not provided	2018-12-01	criteria provided, single submitter	clinical testing
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250348	SCV001424668	pathogenic	Retinitis pigmentosa	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.514C>T in the PRPH2 gene has been previously studied(Nichols (1993) Invest Ophthalmol Vis Sci 34 1149). We found this variant in 13 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755792,CM930639). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.514C>T in the PRPH2 gene as a Pathogenic mutation.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250349	SCV001424669	pathogenic	Patterned dystrophy of the retinal pigment epithelium	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.514C>T in the PRPH2 gene has been previously studied(Nichols (1993) Invest Ophthalmol Vis Sci 34 1149). We found this variant in 13 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755792,CM930639). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.514C>T in the PRPH2 gene as a Pathogenic mutation.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250350	SCV001424670	pathogenic	Cone-rod dystrophy	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.514C>T in the PRPH2 gene has been previously studied(Nichols (1993) Invest Ophthalmol Vis Sci 34 1149). We found this variant in 13 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755792,CM930639). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.514C>T in the PRPH2 gene as a Pathogenic mutation.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250351	SCV001424672	pathogenic	Vitelliform macular dystrophy 2	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.514C>T in the PRPH2 gene has been previously studied(Nichols (1993) Invest Ophthalmol Vis Sci 34 1149). We found this variant in 13 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755792,CM930639). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.514C>T in the PRPH2 gene as a Pathogenic mutation.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250352	SCV001424673	pathogenic	Stargardt disease	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.514C>T in the PRPH2 gene has been previously studied(Nichols (1993) Invest Ophthalmol Vis Sci 34 1149). We found this variant in 13 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755792,CM930639). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.514C>T in the PRPH2 gene as a Pathogenic mutation.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000084981	SCV001447838	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV001352972	SCV001548052	likely pathogenic	Patterned macular dystrophy 1	2021-01-30	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002466402	SCV002761618	pathogenic	Retinitis pigmentosa 7	2021-10-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000084981	SCV003930252	pathogenic	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Reported as a common pathogenic variant among individuals of British background (Payne et al., 1998); Published functional studies in mice demonstrate a damaging effect with defective cone photoreceptors and abnormal PRPH2(RDS)/ROM-1 complex formation (Ding et al., 2004; Conley et al., 2014); 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: 21405999, 8747448, 20335603, 32531858, 18055786, 34828423, 10800708, 24463884, 9010868, 8943002, 24608669, 8302543, 8015786, 29343940, 8485576, 7493155, 22183351, 29555955, 19279306, 28838317, 31456290, 32531846, 32036094, 9810570, 33691693, 26667666, 15254014, 9443872, 34411390, 10532447)
Dept Of Ophthalmology, Nagoya University	RCV003887869	SCV004707350	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV003887869	SCV005070996	pathogenic	Retinal dystrophy	2018-01-01	criteria provided, single submitter	clinical testing
SingHealth Duke-NUS Institute of Precision Medicine	RCV001352972	SCV005881540	likely pathogenic	Patterned macular dystrophy 1	2025-02-05	criteria provided, single submitter	clinical testing	Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1). Experimental studies have shown that this missense change affects PRPH2 function (PMID:24463884;15254014). Cosegregation with disease has been found in multiple families in multiple studies (PMID:8747448;20335603;9443872)
OMIM	RCV000014056	SCV000034303	pathogenic	Choroidal dystrophy, central areolar 2	1998-01-01	no assertion criteria provided	literature only
Retina International	RCV000084981	SCV000117117	not provided	not provided		no assertion provided	not provided
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003147	SCV001161216	likely pathogenic	maculopathy	2019-06-23	no assertion criteria provided	research
Leiden Open Variation Database	RCV000084981	SCV001744958	pathogenic	not provided	2021-04-27	no assertion criteria provided	curation	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Global Variome, with Curator vacancy, IMGAG, Julia Lopez, LOVD, Manon Peeters, Yoshito Koyanagi.
Clinical Genetics, Academic Medical Center	RCV000084981	SCV001922523	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000084981	SCV001952194	pathogenic	not provided		no assertion criteria provided	clinical testing