Submissions for variant NM_000322.5(PRPH2):c.554T>C (p.Leu185Pro)

gnomAD frequency: 0.00001  dbSNP: rs121918563

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000084987	SCV000567191	pathogenic	not provided	2017-04-17	criteria provided, single submitter	clinical testing	The L185P variant was reported in 3 families where it functioned as a recessive variant only resultingin a disease phenotype when inherited with a null (loss-of-function) variant in the ROM1 gene ( Kajiwaraet al. 1994). Therefore the L185P variant in the PRPH2 gene and a null variant in the ROM1 genecause a digenic form of retinitis pigmentosa. The L185P substitution has also been reported previously as anapparently homozygous variant in association with Leber congenital amaurosis (Wang et al., 2013). TheL185P variant was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. The L185P variant is a semi-conservative amino acid substitution that occurs at a positionthat is conserved across species. In silico analysis predicts this substitution is probably damaging to theprotein structure/function. Therefore, L185P is interpreted to be a pathogenic variant.
Blueprint Genetics	RCV001075516	SCV001241142	pathogenic	Retinal dystrophy	2018-11-19	criteria provided, single submitter	clinical testing
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250378	SCV001424714	likely pathogenic	Patterned dystrophy of the retinal pigment epithelium	2020-01-07	criteria provided, single submitter	clinical testing	The variant NM_000322.4:c.554T>C in the PRPH2 gene has been previously studied(PMIDs 1684223, 8202715, 10800708, 12925772). We found this variant in 1 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs121918563,CM910323). It is present in gnomAD browser (AF 0.00000812). It is not enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PP1-M, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.554T>C in the PRPH2 gene as a Likely Pathogenic mutation.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000149466	SCV001573365	likely pathogenic	Patterned macular dystrophy 1	2021-04-08	criteria provided, single submitter	research	The PRPH2 c.554T>C variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PP3. Based on this evidence we have classified this variant as Likely Pathogenic.
Invitae	RCV001378481	SCV001576053	pathogenic	PRPH2-Related Disorders	2023-06-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PRPH2 function (PMID: 8943002, 11297544, 11427722, 12925772). 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: 13165). This missense change has been observed in individuals with autosomal recessive and autosomal dominant retinal dystrophy. This variant may be associated with a milder, later-onset form of autosomal dominant retinal dystrophy (PMID: 1684223, 8202715, 9331261, 16799052, 23847139, 26720483, 32531846; Invitae). This variant is present in population databases (rs121918563, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 185 of the PRPH2 protein (p.Leu185Pro).
OMIM	RCV000014051	SCV000034298	pathogenic	Retinitis pigmentosa 7, digenic	2013-10-01	no assertion criteria provided	literature only
Retina International	RCV000084987	SCV000117123	not provided	not provided		no assertion provided	not provided
OMIM	RCV000149464	SCV000196108	pathogenic	Leber congenital amaurosis 18	2013-10-01	no assertion criteria provided	literature only
OMIM	RCV000149466	SCV000196110	pathogenic	Patterned macular dystrophy 1	2013-10-01	no assertion criteria provided	literature only
Leiden Open Variation Database	RCV001530305	SCV001745074	likely pathogenic	Retinitis pigmentosa	2021-04-06	no assertion criteria provided	curation	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Feng Wang, Julia Lopez, Manon Peeters.