ClinVar Miner

Submissions for variant NM_000326.5(RLBP1):c.700C>T (p.Arg234Trp) (rs28933990)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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 RCV001286635 SCV001473243 likely pathogenic none 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 2020-08-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 234 of the RLBP1 protein (p.Arg234Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs28933990, ExAC 0.05%). This variant has been observed in individual(s) with Bothnia retinal dystrophy (PMID: 10102298, 22171637). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13100). This variant has been reported to affect RLBP1 protein function (PMID: 19846785). For these reasons, this variant has been classified as Pathogenic.
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

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