dbSNP rs786205626: RLBP1:p.Phe96_Phe99del (chr15-89217168-TGAAGCGCAGGAA-T) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM4PP3PP5_Very_Strong

The NM_000326.5(RLBP1):c.286_297delTTCCTGCGCTTC(p.Phe96_Phe99del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RLBP1
NM_000326.5 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 8.62

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000326.5.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 15-89217168-TGAAGCGCAGGAA-T is Pathogenic according to our data. Variant chr15-89217168-TGAAGCGCAGGAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89217168-TGAAGCGCAGGAA-T is described in Lovd as [Likely_pathogenic]. Variant chr15-89217168-TGAAGCGCAGGAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RLBP1	NM_000326.5 link	c.286_297delTTCCTGCGCTTC	p.Phe96_Phe99del	conservative_inframe_deletion	Exon 5 of 9	ENST00000268125.10	NP_000317.1	P12271
RLBP1	XM_011521870.3 link	c.286_297delTTCCTGCGCTTC	p.Phe96_Phe99del	conservative_inframe_deletion	Exon 5 of 9		XP_011520172.1	P12271
RLBP1	XM_047432927.1 link	c.286_297delTTCCTGCGCTTC	p.Phe96_Phe99del	conservative_inframe_deletion	Exon 3 of 7		XP_047288883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RLBP1	ENST00000268125.10 link	c.286_297delTTCCTGCGCTTC	p.Phe96_Phe99del	conservative_inframe_deletion	Exon 5 of 9	1	NM_000326.5	ENSP00000268125.5		P12271
RLBP1	ENST00000567787.1 link	n.183+103_183+114delTTCCTGCGCTTC		intron_variant	Intron 5 of 7	5		ENSP00000457251.1		H3BTN3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250780

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135644

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461762

Hom.:

AF XY:

0.00000413

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bothnia retinal dystrophy

Pathogenic:2

Feb 04, 2014

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This inframe deletion in the non-repeat region can change the length of the protein and disrupt protein function (PM4_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000191289, PMID:26355662, 3billion dataset).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.286_297del, results in the deletion of 4 amino acid(s) of the RLBP1 protein (p.Phe96_Phe99del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs786205626, gnomAD 0.0009%). This variant has been observed in individual(s) with clinical features of retinitis punctata albescens (PMID: 25326637, 26355662, 32188692). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 191289). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy

Pathogenic:2

Jan 01, 2021

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 16, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive retinitis pigmentosa

Pathogenic:1

Sep 10, 2015

Faculty of Health Sciences, Beirut Arab University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Abnormality of the eye

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis punctata albescens

Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Retinitis pigmentosa

Pathogenic:1

Dec 31, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RLBP1 c.286_297del12 (p.Phe96_Phe99del) results in an in-frame deletion that is predicted to remove 4 amino acids from the encoded protein. The variant allele was found at a frequency of 4e-06 in 250780 control chromosomes. c.286_297del12 has been reported in the literature in the compound heterozygous or homozygous state in multiple individuals affected with retinal dystrophies (example, Lee_2014, Lima_2020, Patel_2016), including at least 1 family where this variant segregated with disease and was in trans with a pathogenic variant. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25326637, 32188692, 26355662). ClinVar contains an entry for this variant (Variation ID: 191289). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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