RBM20

protein-coding

RNA binding motif protein 20, the group of RNA binding motif containing

Gene summary

This gene encodes a protein that binds RNA and regulates splicing. Mutations in this gene have been associated with familial dilated cardiomyopathy. [provided by RefSeq, Apr 2014]

MANE transcript

NM_001134363.3

Inheritance

ClinVar variants

P:161U:964B:900

Top phenotype

Cardiomyopathy, dilated, 1DD

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr10:110,644,336-110,839,471

External References & Databases

Ensembl (ENSG00000203867)

Transcript & Mutation Effects

hg38 • Region Span ~195.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dilated cardiomyopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: ClinGen

RBM20 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2009 (Brauch et al, 2009, PMID: 19712804). To date, a large number of studies have reported over 25 RBM20 variants in DCM patients (Key papers include 26084686, Hey et al, 2019, PMID: 30871348; Li et al, 2010, PMID: 20590677; Millat et al, 2011, PMID: 21846512). Human evidence supporting this gene-disease relationship includes case-level data and segregation data, including 55 index cases with DCM carrying RBM20 variants. Brauch et al (2009, PMID: 19712804) performed linkage analysis on two large DCM families to identify RBM20 as the disease locus and subsequent screening of 8 DCM families identified a total of 5 RBM20 variants (p.Pro638Leu, p.Arg636His, p.Arg636Ser, p.Ser637Gly, p.Arg634Gln). In addition, this gene-disease association is supported by experimental evidence reported in several studies. In particular, Beqqali et al (2016, PMID: 27496873) performed functional studies on the p.E913K variant. They investigated human cardiac tissue with p.E913K and U-2 OS transfected cells and observed down-regulation of the RBM20 protein by Western blot. They also showed by RNA-seq analysis that p.E913K affects titin splicing. In RBM20 deficient rats, the observed phenotype resembled human DCM with arrhythmia and sudden cardiac death (Guo et al, 2012, PMID: 22466703). The same study also identified the p.S635A variant which in splice reporter assays rendered RBM20 inactive. Human induced pluripotent stem cells (iPSC) carrying the p.S636A variant showed abnormal distribution of alpha-actinin and defective calcium handling (Streckfuss-Bömekeet al, 2017, PMID: 28941705). Gene expression analysis in iPSCs carrying the p.S636A variant showed dysregulated sarcomeric (TTN and LDB3) and calcium handling (CAMK2D and CACNA1C) genes (Oishi et al, 2016, PMID: 26604126). In summary, there is strong evidence to support the relationship between RBM20 and autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Therefore, the classification has been revised to definitive. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on October 11, 2019 (SOP Version 7).

dilated cardiomyopathy 1DDSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013168

Submitter: Labcorp Genetics (formerly Invitae)

familial isolated dilated cardiomyopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

dilated cardiomyopathy 1DDSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013168

Submitter: Ambry Genetics

familial hypertrophic cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: G2P

dilated cardiomyopathy 1DDSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013168

Submitter: PanelApp Australia

dilated cardiomyopathy 1DDDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013168

Submitter: G2P

hypertrophic cardiomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

RBM20 was first reported in relation to autosomal dominant HCM in 2021 (Dai et al. PMID: 34333030). At least 13 variants (e.g. missense, splice acceptor, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes only case-level data. Variants in this gene have been reported in at least 13 probands in 1 publication (PMID: 34333030). Additionally, there are families described in the literature with no segregation of RBM20 variants with HCM phenotype; these publications were not scored. There are no publications showing a clear segregation of RBM20 variants with HCM in family members. The mechanism for disease is unknown. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel on October 26, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Cardiomyopathy, dilated, 1DDAD

Manifestation: Cardiovascular

Intervention: Cardiovascular

Rationale: Surveillance (eg, with echocardiography and electrocardiography), preventive measures and medical management may help decrease morbidity; Cardiac transplantation has been described

Refs: 19712804; 20590677; 21846512

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RBM20 variants in ClinVar

23 Conditions Cataloged

Dilated cardiomyopathy 1DDTotal: 1864

Cardiovascular phenotypeTotal: 980

not providedTotal: 460

not specifiedTotal: 283

CardiomyopathyTotal: 113

Primary dilated cardiomyopathyTotal: 36

RBM20-related disorderTotal: 32

Hypertrophic cardiomyopathyTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001134363.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			10 clinvar	562 clinvar	10 clinvar	582
missense	4 clinvar	22 clinvar	919 clinvar	318 clinvar	9 clinvar	1272
nonsense	29 clinvar	18 clinvar	11 clinvar			58
start loss						0
frameshift	39 clinvar	30 clinvar	21 clinvar	1 clinvar		91
splice donor/acceptor (+/-2bp)		19 clinvar	3 clinvar			22
Total	72	89	964	881	19	2025

Highest pathogenic variant AF is 0.000032223637

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001134363.3	RefSeq	NP_001127835.2	14	MANE Select
ENST00000369519.4	Ensembl	ENSP00000358532.3	14	MANE Select
ENST00000718239.1	Ensembl	ENSP00000520684.1	14	Standard
ENST00000718239.2	Ensembl	ENSP00000520684.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mRNA processing
heart development
RNA splicing
positive regulation of RNA splicing

Molecular Function

RNA binding
zinc ion binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369519
Coding exons: 14
Length: 195073
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.67	543	664	0.818	0.0000376	7995
Missense (PolyPhen)		184	246.54	0.74633		2879
Synonymous	2.10	226	270	0.837	0.0000165	2450
Loss of Function	5.22	7	44.6	0.157	0.00000218	575

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: RNA-binding protein that acts as a regulator of mRNA splicing of a subset of genes involved in cardiac development. Regulates splicing of TTN (Titin). {ECO:0000269|PubMed:22466703}.;

Intolerance Scores

RVIS EVS: 1.02
RVIS percentile EVS: 90.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.140

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium