Submissions for variant NM_014014.5(SNRNP200):c.2041C>T (p.Arg681Cys)

dbSNP: rs959069360

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000787717	SCV001135920	pathogenic	Retinitis pigmentosa	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002103	SCV001159950	likely pathogenic	Retinitis pigmentosa 33	2018-09-25	criteria provided, single submitter	clinical testing	The SNRNP200 c.2041C>T; p.Arg681Cys variant (rs959069360) is reported in the medical literature segregating with disease in at least three families with autosomal dominant retinitis pigmentosa (Benaglio 2011, Bowne 2013). The variant is found in the general population in 1 out of 246188 alleles, indicating it is not a common polymorphism. The arginine at this position is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Additionally, other protein variants in the same codon, p.Arg681His and p.Arg681Leu, have been described in individuals with retinitis pigmentosa (Benaglio 2011, Bowne 2013, de Castro-Miro 2014). Considering available information, this variant is classified as likely pathogenic. Pathogenic SNRNP200 are causative for autosomal dominant retinitis pigmentosa (MIM: 610359). References: Benaglio P et al. Next generation sequencing of pooled samples reveals new SNRNP200 mutations associated with retinitis pigmentosa. Hum Mutat. 2011 Jun;32(6):E2246-58 Bowne SJ et al. Mutations in the small nuclear riboprotein 200 kDa gene (SNRNP200) cause 1.6% of autosomal dominant retinitis pigmentosa. Mol Vis. 2013 Nov 24;19:2407-17. eCollection 2013. de Castro-Miro M et al. Combined genetic and high-throughput strategies for molecular diagnosis of inherited retinal dystrophies. PLoS One. 2014 Feb 7;9(2):e88410.
Invitae	RCV001042854	SCV001206560	pathogenic	not provided	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 681 of the SNRNP200 protein (p.Arg681Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (adRP) (PMID: 21618346, 28076437). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 636112). 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 SNRNP200 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg681 amino acid residue in SNRNP200. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21618346, 24940031, 28076437, 30360737). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001042854	SCV001248169	pathogenic	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001042854	SCV001446947	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000787717	SCV001950381	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Arg681Cys variant in SNRNP200 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PP1-S, PM1. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Dept Of Ophthalmology, Nagoya University	RCV003889983	SCV004705443	likely pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787717	SCV000926709	likely pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001042854	SCV001958510	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001042854	SCV001965988	pathogenic	not provided		no assertion criteria provided	clinical testing