Submissions for variant NM_000322.5(PRPH2):c.367C>T (p.Arg123Trp)

gnomAD frequency: 0.00019  dbSNP: rs563581127

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000403427	SCV000339062	uncertain significance	not provided	2016-01-29	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000791184	SCV000930465	uncertain significance	PRPH2-related disorder	2019-04-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001165007	SCV001327171	uncertain significance	Patterned macular dystrophy 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001165008	SCV001327172	uncertain significance	Retinitis pigmentosa	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001165009	SCV001327173	uncertain significance	Adult-onset foveomacular vitelliform dystrophy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001165010	SCV001327174	uncertain significance	Choroidal dystrophy, central areolar 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001165011	SCV001327175	uncertain significance	Pigmentary retinal dystrophy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001165012	SCV001327176	uncertain significance	Cone-rod dystrophy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791184	SCV001576972	pathogenic	PRPH2-related disorder	2023-09-25	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 123 of the PRPH2 protein (p.Arg123Trp). This variant is present in population databases (rs563581127, gnomAD 0.1%). This missense change has been observed in individuals with autosomal dominant inherited retinal dystrophy (PMID: 16767206, 19038374; Invitae). ClinVar contains an entry for this variant (Variation ID: 285861). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV004720250	SCV005329340	uncertain significance	Retinitis pigmentosa 7	2023-05-20	criteria provided, single submitter	clinical testing	The missense c.367C>T (p.Arg123Trp) variant in the PRPH2 gene has been reported previously in patients affected with Retinal pigmentosa (Peeters, Manon H C A et al.,2021). Also, the variant has been reported previously in patients affected withUsher syndrome (Ng, Tsz Kin et al.,2019) and observed in a pair of twins with autosomal dominant inherited retinal dystrophy (Renner, Agnes B et al.,2009). This variant is reported with the allele frequency (0.02%) in the gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic/Uncertain Significance (multiple submissions). The amino acid Arginine at position 123 is changed to a Trptophan changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant.The amino acid change p.Arg123Trp in PRPH2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Additional studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Uncertain Significance.
Leiden Open Variation Database	RCV000403427	SCV001744950	likely pathogenic	not provided	2021-04-06	no assertion criteria provided	curation	Curator: Global Variome, with Curator vacancy. Submitter to LOVD: Manon Peeters.