Submissions for variant NM_000322.5(PRPH2):c.629C>G (p.Pro210Arg)

dbSNP: rs61755798

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000322776	SCV000463270	likely pathogenic	PRPH2-Related Disorders	2018-09-26	criteria provided, single submitter	clinical testing	The PRPH2 c.629C>G (p.Pro210Arg) variant is a missense variant that has been reported in four studies, where it was found in a total of six individuals with PRPH2-related disorders, including one homozygote and five heterozygotes (Feist et al. 1994; Gorin et al. 1995; Zhuk et al. 2006; Duncan et al. 2011). The family of one individual reported by Gorin et al. (1995) included at least 10 affected and three unaffected individuals who carried the variant, demonstrating unclear segregation. The p.Pro210Arg variant was absent from 127 controls in the above studies, and it is not reported in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium despite being located in a region of good sequencing coverage. Therefore, the variant is presumed to be rare. Based on the evidence, the p.Pro210Arg variant is classified as likely pathogenic for PRPH2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000322776	SCV001199773	pathogenic	PRPH2-Related Disorders	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 210 of the PRPH2 protein (p.Pro210Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinal disease (PMID: 7862413, 11139241, 17504850). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13173). 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%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074849	SCV001240450	pathogenic	Retinal dystrophy	2019-07-24	criteria provided, single submitter	clinical testing
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250286	SCV001424598	pathogenic	Stargardt disease	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.629C>G in the PRPH2 gene has been previously studied(PMIDs 7519821, 25082885). We found this variant in 7 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755798,CM941210). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM1, PM2, PM5, PP3, PP5] and classified NM_000322.4:c.629C>G in the PRPH2 gene as a Pathogenic mutation.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250287	SCV001424599	pathogenic	Patterned dystrophy of the retinal pigment epithelium	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.629C>G in the PRPH2 gene has been previously studied(PMIDs 7519821, 25082885). We found this variant in 7 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755798,CM941210). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM1, PM2, PM5, PP3, PP5] and classified NM_000322.4:c.629C>G in the PRPH2 gene as a Pathogenic mutation.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250288	SCV001424600	pathogenic	Vitelliform macular dystrophy 2	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.629C>G in the PRPH2 gene has been previously studied(PMIDs 7519821, 25082885). We found this variant in 7 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755798,CM941210). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM1, PM2, PM5, PP3, PP5] and classified NM_000322.4:c.629C>G in the PRPH2 gene as a Pathogenic mutation.
GeneDx	RCV000084997	SCV002102623	pathogenic	not provided	2022-03-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7519821, 17504850, 11139241, 25082885, 16885924, 21071739, 16799052, 22863181, 7862413, 32531846)
OMIM	RCV002508119	SCV000034306	pathogenic	Vitelliform macular dystrophy 3	1995-02-01	no assertion criteria provided	literature only
Retina International	RCV000084997	SCV000117133	not provided	not provided		no assertion provided	not provided
Leiden Open Variation Database	RCV000084997	SCV001745089	likely pathogenic	not provided	2021-04-06	no assertion criteria provided	curation	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Julia Lopez, Manon Peeters.