3-25596428-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_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. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
RARB
NM_000965.5 missense
NM_000965.5 missense
Scores
12
4
1
Clinical Significance
Conservation
PhyloP100: 6.17
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]
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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;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RARB. . Gene score misZ 2.8661 (greater than the threshold 3.09). Trascript score misZ 3.1257 (greater than threshold 3.09). GenCC has associacion of gene with 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 [Likely_pathogenic]. Clinvar id is 88762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-25596428-C-T is described in Lovd as [Pathogenic]. Variant chr3-25596428-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RARB | NM_000965.5 | c.1159C>T | p.Arg387Cys | missense_variant | 8/8 | ENST00000330688.9 | NP_000956.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RARB | ENST00000330688.9 | c.1159C>T | p.Arg387Cys | missense_variant | 8/8 | 1 | NM_000965.5 | ENSP00000332296.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microphthalmia, syndromic 12 Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 31, 2022 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects RARB function (PMID: 24075189). 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. ClinVar contains an entry for this variant (Variation ID: 88762). 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. This variant is not present in population databases (gnomAD no frequency). 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 13, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 03, 2013 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 25, 2021 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | Daryl Scott Lab, Baylor College of Medicine | Nov 10, 2023 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2022 | 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Vest4
0.78, 0.81, 0.78
MutPred
Loss of MoRF binding (P = 0.0024);.;.;.;
MVP
MPC
2.2
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at