rs28933990

chr15-89210794-G-Achr15-89210794-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000326.5(RLBP1):c.700C>T(p.Arg234Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000661 in 1,436,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R234Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: RLBP1 NM_000326.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.29

Genes affected

RLBP1 (HGNC:10024): (retinaldehyde binding protein 1) The protein encoded by this gene is a 36-kD water-soluble protein which carries 11-cis-retinaldehyde or 11-cis-retinal as physiologic ligands. It may be a functional component of the visual cycle. Mutations of this gene have been associated with severe rod-cone dystrophy, Bothnia dystrophy (nonsyndromic autosomal recessive retinitis pigmentosa) and retinitis punctata albescens. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain CRAL-TRIO (size 161) in uniprot entity RLBP1_HUMAN there are 24 pathogenic changes around while only 4 benign (86%) in NM_000326.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 15-89210794-G-A is Pathogenic according to our data. Variant chr15-89210794-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89210794-G-A is described in Lovd as [Pathogenic]. Variant chr15-89210794-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RLBP1	NM_000326.5	c.700C>T	p.Arg234Trp	missense_variant	8/9	ENST00000268125.10
RLBP1	XM_011521870.3	c.700C>T	p.Arg234Trp	missense_variant	8/9
RLBP1	XM_047432927.1	c.700C>T	p.Arg234Trp	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RLBP1	ENST00000268125.10	c.700C>T	p.Arg234Trp	missense_variant	8/9	1	NM_000326.5	P1
RLBP1	ENST00000563254.1	c.102-30C>T		intron_variant		2
RLBP1	ENST00000567787.1	c.*278C>T		3_prime_UTR_variant, NMD_transcript_variant	8/8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000860 AC: 18 AN: 209368 Hom.: 0 AF XY: 0.0000804 AC XY: 9 AN XY: 111996

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000661 AC: 95 AN: 1436926 Hom.: 0 Cov.: 31 AF XY: 0.0000632 AC XY: 45 AN XY: 712324

Gnomad4 AFR exome AF: 0.0000605

Gnomad4 AMR exome AF: 0.0000239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000844

Gnomad4 FIN exome AF: 0.0000581

Gnomad4 NFE exome AF: 0.0000619

Gnomad4 OTH exome AF: 0.000219

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000502 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.000198 AC: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 21, 2023	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2019	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. -

Retinitis pigmentosa Pathogenic:2

Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2023	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. -

Bothnia retinal dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2001

- -

RLBP1-Related Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

Retinitis punctata albescens Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2001

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.85
MPC		0.85
ClinPred		0.99	D
GERP RS		1.9
Varity_R		0.93
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28933990; hg19: chr15-89754025;