rs137853291

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000326.5(RLBP1):c.677T>A(p.Met226Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,613,766 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M226L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

RLBP1
NM_000326.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 8.93

Variant links:

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]

RLBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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, 0.901

PP5

Variant 15-89211750-A-T is Pathogenic according to our data. Variant chr15-89211750-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 13101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89211750-A-T is described in Lovd as [Pathogenic]. Variant chr15-89211750-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RLBP1	NM_000326.5 linkuse as main transcript	c.677T>A	p.Met226Lys	missense_variant	7/9	ENST00000268125.10
RLBP1	XM_011521870.3 linkuse as main transcript	c.677T>A	p.Met226Lys	missense_variant	7/9
RLBP1	XM_047432927.1 linkuse as main transcript	c.677T>A	p.Met226Lys	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
RLBP1	ENST00000268125.10 linkuse as main transcript	c.677T>A	p.Met226Lys	missense_variant	7/9	1	NM_000326.5	P1
RLBP1	ENST00000563254.1 linkuse as main transcript	c.95T>A	p.Met32Lys	missense_variant	1/3	2
RLBP1	ENST00000567787.1 linkuse as main transcript	c.*255T>A		3_prime_UTR_variant, NMD_transcript_variant	7/8	5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251440

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000967

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000903

AC:

132

AN:

1461576

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000694

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 226 of the RLBP1 protein (p.Met226Lys). This variant is present in population databases (rs137853291, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of retinitis punctata albescens (PMID: 10102299, 22551409). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as M225K. ClinVar contains an entry for this variant (Variation ID: 13101). 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 RLBP1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RLBP1 function (PMID: 12536144). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 02, 2023	Variant summary: RLBP1 c.677T>A (p.Met226Lys) results in a non-conservative amino acid change located in the CRAL-TRIO lipid binding domain (IPR001251) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251440 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RLBP1 causing Retinitis Pigmentosa (4.4e-05 vs 0.00063), allowing no conclusion about variant significance. c.677T>A has been reported in the literature in many compound heterozygous and homozygous individuals affected with Retinitis Pigmentosa and was shown to segregate with disease in related individuals (e.g., Kohn_2008, Morimura_1999, Thorsteinsson_2021). 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: 18344446, 10102299, 33851411). Five ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic (n = 4) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. -

RLBP1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The RLBP1 c.677T>A (p.Met226Lys) missense variant has been reported in three studies in which it is found in a total of 25 patients with RLBP1-related disorders including in four patients in a homozygous state and in 21 patients in a compound heterozygous state (Morimura et al. 1999; KÃ¶hn et al. 2008; Burstedt et al. 2013). The p.Met226Lys variant was also found in two unaffected family members in a heterozygous state. The variant was present in a heterozygous state in one of 303 control samples and is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression in E.coli showed that the p.Met226Lys variant is less soluble than the wild type protein; NMR analysis of the protein structure showed that the variant protein has structural differences in comparison to wild type; UV-visible spectral analysis of purified protein showed that the variant protein has no cis-retinoid binding capacity for either 9-cis-retinal or 11-cis retinal. Overall the functional studies showed that the p.Met226Lys variant protein abolishes retinoid binding and impairs function of the protein in the visual cycle as an 11-cis retinol acceptor and substrate carrier (Golovleva et al. 2003). Based on the collective evidence, the p.Met226Lys 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

Apr 01, 1999

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jun 17, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.25

Cadd

Pathogenic

Dann

Uncertain

0.98

DEOGEN2

Pathogenic

0.84

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.081

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.70

Sift

Benign

0.11

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.98

MVP

0.85

MPC

1.0

ClinPred

0.36

GERP RS

5.5

Varity_R

0.95

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over