Submissions for variant NM_000326.5(RLBP1):c.700C>T (p.Arg234Trp)

dbSNP: rs28933990

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000345884	SCV000394105	pathogenic	RLBP1-Related Disorders	2017-04-28	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the RLBP1 c.700C>T (p.Arg234Trp) missense variant has been identified in a homozygous state in 89 patients and in a compound heterozygous state in 11 patients with RLBP1-related disorders (Burstedt et al. 1999; Morimura et al. 1999; Nakamura et al. 2005; Golovleva et al. 2010; Hipp et al. 2015). The p.Arg234Trp variant was reported in six out of 588 control chromosomes and is reported at a frequency of 0.00047 in the European (non-Finnish) population of the Exome Aggregation Consortium. The crystal structure of the variant protein bound to its endogenous ligand, 11-cis-retinal, was compared with the crystal structure of the wild type protein similarly bound to 11-cis-retinal (He et al. 2009; He et al. 2012). The structural analysis revealed an altered retinoid binding pocket in the p.Arg234Trp variant protein, which resulted in a 5-fold tighter binding of the variant protein to 11-cis-retinal, and hence impaired release, compared to wild type (Golovleva et al. 2003). Based on the collective evidence, the p.Arg234Trp variant is classified as pathogenic for RLBP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001387783	SCV001473243	likely pathogenic	not provided	2019-09-04	criteria provided, single submitter	clinical testing	The RLBP1 c.700C>T; p.Arg234Trp (rs28933990) variant is reported in several individuals and families with retinal dystrophy (Burstedt 1999, Granse 2001, Hipp 2015, Morimura 1999, Nakamura 2005). The variant is reported as pathogenic in ClinVar (Variation ID: 13100) and is reported in the general population with an overall allele frequency of 0.009% (18/209,368 alleles) in the Genome Aggregation Database. The arginine at codon 234 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. References: Burstedt MS et al. Bothnia dystrophy caused by mutations in the cellular retinaldehyde-binding protein gene (RLBP1) on chromosome 15q26. Invest Ophthalmol Vis Sci. 1999 Apr;40(5):995-1000. Granse L et al. Electrophysiological findings in two young patients with Bothnia dystrophy and a mutation in the RLBP1 gene. Ophthalmic Genet. 2001 Jun;22(2):97-105. Hipp S et al. Phenotype variations of retinal dystrophies caused by mutations in the RLBP1 gene. Acta Ophthalmol. 2015 Jun;93(4):e281-6. Morimura H et al. Recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens. Invest Ophthalmol Vis Sci. 1999 Apr;40(5):1000-4. Nakamura M et al. Novel mutation in RLBP1 gene in a Japanese patient with retinitis punctata albescens. Am J Ophthalmol. 2005 Jun;139(6):1133-5.
Invitae	RCV001387783	SCV001588499	pathogenic	not provided	2023-09-21	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 RLBP1 function (PMID: 19846785). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RLBP1 protein function. ClinVar contains an entry for this variant (Variation ID: 13100). This missense change has been observed in individuals with Bothnia retinal dystrophy (PMID: 10102298, 22171637). It is commonly reported in individuals of Swedish ancestry (PMID: 10102298). This variant is present in population databases (rs28933990, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 234 of the RLBP1 protein (p.Arg234Trp).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001003174	SCV004039157	pathogenic	Retinitis pigmentosa	2023-08-02	criteria provided, single submitter	clinical testing	Variant summary: RLBP1 c.700C>T (p.Arg234Trp) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the CRAL-TRIO lipid binding domain (IPR001251) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.6e-05 in 209368 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RLBP1 causing Retinitis Pigmentosa (8.6e-05 vs 0.00063), allowing no conclusion about variant significance. c.700C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa or Bothnia dystrophy with strong evidence of cosegregation with disease (Sharon_2019, Burstedt_1999, Kohn_2008), and some were reported as compound heterozygous with another pathogenic variant. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 31456290, 10102298, 18344446). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Dept Of Ophthalmology, Nagoya University	RCV003887865	SCV004704923	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
OMIM	RCV000013978	SCV000034225	pathogenic	Bothnia retinal dystrophy	2001-06-01	no assertion criteria provided	literature only
OMIM	RCV000013979	SCV000034226	pathogenic	Retinitis punctata albescens	2001-06-01	no assertion criteria provided	literature only
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003174	SCV001161250	pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research