3-25596428-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000965.5(RARB):c.1159C>T(p.Arg387Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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. R387S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

RARB
NM_000965.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 6.17

Publications

11 publications found

Variant links:

Genes affected

RARB (HGNC:9865): (retinoic acid receptor beta) This gene encodes retinoic acid receptor beta, a member of the thyroid-steroid hormone receptor superfamily of nuclear transcriptional regulators. This receptor localizes to the cytoplasm and to subnuclear compartments. It binds retinoic acid, the biologically active form of vitamin A which mediates cellular signalling in embryonic morphogenesis, cell growth and differentiation. It is thought that this protein limits growth of many cell types by regulating gene expression. The gene was first identified in a hepatocellular carcinoma where it flanks a hepatitis B virus integration site. Alternate promoter usage and differential splicing result in multiple transcript variants. [provided by RefSeq, Mar 2014]

RARB Gene-Disease associations (from GenCC):

microphthalmia, syndromic 12
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Baylor College of Medicine Research Center
Matthew-Wood syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RARB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-25596428-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 88763.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the RARB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 2.8661 (below the threshold of 3.09). Trascript score misZ: 3.1257 (above the threshold of 3.09). GenCC associations: The gene is linked to microphthalmia, syndromic 12, Matthew-Wood syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

PP5

Variant 3-25596428-C-T is Pathogenic according to our data. Variant chr3-25596428-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 88762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5 link	c.1159C>T	p.Arg387Cys	missense_variant	Exon 8 of 8	ENST00000330688.9	NP_000956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9 link	c.1159C>T	p.Arg387Cys	missense_variant	Exon 8 of 8	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microphthalmia, syndromic 12

Pathogenic:8

Aug 13, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 03, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

May 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg387 amino acid residue in RARB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24075189). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RARB function (PMID: 24075189). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 387 of the RARB protein (p.Arg387Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with microphthalmia (PMID: 24075189, 27120018). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 88762). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive.

Sep 01, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.87). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals, and observed in at least two similarly affected unrelated individuals (PMID: 24075189). Different missense changes at the same codon (p.Arg387Leu, p.Arg387Ser) have been reported to be associated with RARB-related disorder (ClinVar ID: VCV000088763 , VCV000430023 / PMID: 24075189). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS2, PS3, PS4, PM2, PM5, PP3

Mar 14, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Pathogenic:1

Aug 25, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1159C>T (p.R387C) alteration is located in exon 8 (coding exon 8) of the RARB gene. This alteration results from a C to T substitution at nucleotide position 1159, causing the arginine (R) at amino acid position 387 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The p.R387C alteration has been identified in three cases with features of anophthalmia/microphthalmia, severe developmental delay, progressive spasticity, Chiari I malformation, and feeding difficulties (Srour, 2013; Slavotinek, 2015). Srour et al. (2013) identified this de novo missense change in a fetus that was terminated because of a prenatal diagnosis of unilateral microphthalmia and left diaphragmatic hernia and also in a newborn who died within hours of birth with left diaphragmatic hernia, bilateral microphthalmia, and pulmonary hypoplasia. Slavotinek et al. (2015) reported a de novo p.R387C alteration in a patient with bilateral microphthalmia and unilateral coloboma, left diaphragmatic hernia, cleft palate, and a Chiari I malformation. Another variant at the same codon, p.R387S, has been identified in one individual with bilateral microphthalmia, corrected diaphragmatic hernia, intellectual disability, and spasticity (Chitayat, 2007; Srour, 2013). This amino acid position is highly conserved in available vertebrate species. The p.R387C amino acid is located in helix 11 of the C-terminal ligand-binding domain (Srour, 2013). When a ligand binds, the ligand-binding domain undergoes a conformational change in the receptor to induce a response, which serves as a molecular switch to activate transcriptional activity (Edwards, 2000). Functional analysis demonstrated that the p.R387C alteration induced a 2- to 3-fold increase in RARB transcriptional activity in response to retinoic acid ligands, suggestive of a gain-of-function mechanism (Srour, 2013). Functional analysis in transfected HEK293 cells demonstrated that the transcriptional response to retinoic acid was significantly increased, reaching a 28-fold induction for the p.R387C mutant compared to 9-fold for wildtype RARB (Srour, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Intellectual disability, autosomal dominant 48

Pathogenic:1

Nov 10, 2023

Daryl Scott Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1

Mar 02, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a gain-of-function effect on the resultant protein (Srour et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24075189, 25457163, 27120018, 30790422, 30480585)

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;.;.;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

1.0

D;.;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

6.2

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.6

D;D;D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Vest4

0.0

ClinPred

0.99

GERP RS

5.8

gMVP

0.64

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over