Submissions for variant NM_000322.5(PRPH2):c.748T>A (p.Cys250Ser)

dbSNP: rs1064793931

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479139	SCV000567373	pathogenic	not provided	2015-08-20	criteria provided, single submitter	clinical testing	The C250S missense variant has not been published as a pathogenic variant, nor has it been reported as a benignpolymorphism to our knowledge. In vitro functional studies demonstrated that replacing the conservedCysteine at amino acid 250 with a Serine residue leads to protein misfolding and prevents tetramerformation (Goldberg et al. 1998). The C250S substitution was not observed in approximately 6,500 individualsof European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations. The C250S variant is a non-conservative amino acidsubstitution that occurs at a position that is conserved across species. In silico analysis predicts this variantis probably damaging to the protein structure/function. Another missense variant in this residue (C250F)and other missense variants nearby residues (N244H, N244K, W246R, W246C, G249S, A253D, L254Q)have been reported in the Human Gene Mutation Database in association with PRPH2-related disorders(Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret C250S as a pathogenic variant.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250338	SCV001424658	likely pathogenic	Stargardt disease	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.748T>A in the PRPH2 gene has not been reported to our knowledge . We found this variant in 1 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is not listed in dbSNP and/or HGMD. It is absent in gnomAD browser. It is not enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PM2, PM4, PP3, PP5] and classified NM_000322.4:c.748T>A in the PRPH2 gene as a Likely Pathogenic mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525801	SCV002969036	pathogenic	PRPH2-related disorder	2022-10-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys250 amino acid residue in PRPH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16113362). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 419521). This missense change has been observed in individual(s) with Stargardt disease (PMID: 32531846; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 250 of the PRPH2 protein (p.Cys250Ser).
Leiden Open Variation Database	RCV000479139	SCV001745181	likely pathogenic	not provided	2021-04-06	no assertion criteria provided	curation	Curator: Global Variome, with Curator vacancy. Submitter to LOVD: Manon Peeters.