Submissions for variant NM_178857.6(RP1L1):c.133C>T (p.Arg45Trp)

gnomAD frequency: 0.00001  dbSNP: rs267607017

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726920	SCV000704172	likely pathogenic	not provided	2016-12-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000002277	SCV000916218	uncertain significance	Occult macular dystrophy	2017-08-22	criteria provided, single submitter	clinical testing	The RP1L1 c.133C>T (p.Arg45Trp) missense variant has been reported in at least six studies and is found in a heterozygous state in a total of 35 individuals with occult macular dystrophy, including 15 unrelated individuals. The variant is also found in 13 unaffected family members (Akahori et al. 2010; Okuno et al. 2013; Hayashi et al. 2012; Davidson et al. 2013; Piermarocchi et al. 2016; Fujinami al. 2016). Due to the presence of both affected and unaffected family members carrying the p.Arg45Trp variant in a heterozygous state, Akahori et al. (2010) and Davidson et al. (2013) suggest that the variant may exhibit reduced penetrance or later age of onset in asymptomatic carriers. The p.Arg45Trp variant was absent from 976 controls but is reported at a frequency of 0.000025 in the total population of the Genome Aggregation Database. Based on the evidence, the p.Arg45Trp variant is classified a variant of unknown significance but suspicious for pathogenicity for occult macular dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Blueprint Genetics	RCV001074376	SCV001239954	pathogenic	Retinal dystrophy	2019-07-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726920	SCV001245752	likely pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	RP1L1: PP1:Strong, PS4:Moderate, PM2:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197672	SCV001368451	pathogenic	Retinitis pigmentosa 88	2019-12-03	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP1-S,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000726920	SCV001447606	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Invitae	RCV000726920	SCV001585398	pathogenic	not provided	2024-01-02	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 45 of the RP1L1 protein (p.Arg45Trp). This variant is present in population databases (rs267607017, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant occult macular dystrophy (PMID: 20826268, 30025130). It has also been observed to segregate with disease in related individuals. This variant is also known as c.362C>T. ClinVar contains an entry for this variant (Variation ID: 2193). 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 not expected to disrupt RP1L1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000726920	SCV001770569	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Reduced penetrance has been reported for the p.(R45W) variant (Zobor et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23281133, 34440443, 32458067, 25908487, 23619761, 26782618, 22466457, 29555955, 28890726, 27579568, 35464678, 32360662, 32176261, 30025130, 20826268, 22504327, 23745001, 27623337, 28195981, 31028767, 31193770, 32940107, 32531858)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000002277	SCV001976392	uncertain significance	Occult macular dystrophy	2022-03-16	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS4_MOD, PP3
MGZ Medical Genetics Center	RCV000002277	SCV002580293	likely pathogenic	Occult macular dystrophy	2021-11-18	criteria provided, single submitter	clinical testing
OMIM	RCV000002277	SCV000022435	risk factor	Occult macular dystrophy	2013-03-01	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000726920	SCV001922196	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000726920	SCV001955747	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000726920	SCV001975316	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000002277	SCV002011783	likely pathogenic	Occult macular dystrophy	2021-08-26	no assertion criteria provided	clinical testing