rs267607001

Positions:

• chr10-110812298-G-A
• chr10-110812298-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_001134363.3(RBM20):​c.1901G>A​(p.Arg634Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,395,174 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R634W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: RBM20 NM_001134363.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.60

Genes affected

RBM20 (HGNC:27424): (RNA binding motif protein 20) 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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a region_of_interest RS (size 27) in uniprot entity RBM20_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_001134363.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-110812297-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831
• PP5: Variant 10-110812298-G-A is Pathogenic according to our data. Variant chr10-110812298-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110812298-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBM20	NM_001134363.3	c.1901G>A	p.Arg634Gln	missense_variant	9/14	ENST00000369519.4	NP_001127835.2
RBM20	XM_017016103.3	c.1736G>A	p.Arg579Gln	missense_variant	9/14		XP_016871592.1
RBM20	XM_017016104.3	c.1517G>A	p.Arg506Gln	missense_variant	9/14		XP_016871593.1
RBM20	XM_047425116.1	c.1517G>A	p.Arg506Gln	missense_variant	9/14		XP_047281072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBM20	ENST00000369519.4	c.1901G>A	p.Arg634Gln	missense_variant	9/14	1	NM_001134363.3	ENSP00000358532	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000656 AC: 1 AN: 152378 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 81174

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000408

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: 0.00

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1395174 Hom.: 0 Cov.: 32 AF XY: 0.00000436 AC XY: 3 AN XY: 687380

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000281

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000799 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 06, 2017	p.Arg634Gln (c.1901G>A) (R634Q) in exon 9 of the RBM20 gene (NM_001134363.1) Given the case data, strong segregation data, supporting in-vitro data, location of the variant in the “hotspot” region of exon 9, and low prevalence in controls, we consider this variant very likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). I checked with LMM, and they have not seen the variant but would classify it as either likely pathogenic or pathogenic (Colleen, 2015). RBM20: Variants in RBM20 are relatively newly-reported with cardiomyopathy and appear to be an infrequent cause of cardiomyopathy (1.9-3.0%) so only minimal data on disease-associated variation in this gene is available. Brauch et al (2009) performed genome-wide linkage analysis in two multi-generational kindreds with DCM, with a LOD score of 3.55. Interestingly, at the time of this study the function of RBM20 was not known, though it was known to be expressed at much higher levels in the heart than in other tissues. Sequencing of the candidate region identified two RBM20 variants, one in each family, that segregated with disease and were absent in 480 controls. They then performed DHLPC analysis of RBM20 in a cohort of 279 DCM patients and identified 6 additional families with RBM20 variants. Hershberger's group used a candidate gene approach, sequencing select RBM20 exons in 312 DCM probands and found rare variants in 6 unrelated patients. RBM20 has been implicated in abnormal TTN splicing and RBM20 deficient mice show signs of cardiomyopathy and arrhythmias (Guo et al 2013). Based on the domains identified in RBM20 it is thought to be an RNA binding protein. Of note, an area in exon 9 appears to be especially susceptible to pathogenic variation. Both variants from the original linkage study were in exon 9. Per an LMM review of the data: "Further study in a larger cohort identified additional variants that all clustered in exon 9, specifically the RS domain. All of these variants segregated with disease and were not identified in controls. This association was further examined by Li and colleagues in 2010, identifying both novel and previously reported variants (Brauch 2009) in the same region of exon 9 in a different cohort of individuals with DCM. More recent studies provide further support for this association (Guo 2012, Refaat 2012). While further study is needed, variants in this particular region of RBM20 appear to be associated with an earlier age of onset, high penetrance, end-stage heart failure and a high mortality." Furthermore, LMM's own internal experience is consistent with the published data: "after 3 years of testing, our laboratory has identified 3 clinically significant variants (classified as pathogenic or likely pathogenic) in this hotspot region of exon 9 in 6 families with DCM; 2 of these families had been previously tested by our laboratory and were negative for any disease-causing variants. All 3 of these variants had been previously reported (Brauch 2009, Li 2010), further supporting that the RS region of exon 9 is likely a hotspot of variation. In addition, the phenotype in these families is consistent with those described previously, which emphasizes the importance and significance of identifying families with disease-causing variation in RBM20 so that the proper management and screening can be implemented." Hershberger's group suggests this is a 5 amino acid hot spot. This region is rich in arginines and serines and is predicted to be involved in protein-protein interactions. Brauch et al (2009) noted a particularly malignant course in families with RBM20 variants, compared to other familial DCM cases. Age of diagnosis of DCM was 9 years younger and many affected individuals died suddenly, needed transplant, or an ICD. Some individuals had left ventricular hypertrophy. While many pedigrees had quite severe disease there was still variability among family members, as -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2022	An in vitro splice reporter assay supports an adverse effect when compared to wild-type (Guo et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26604136, 26187847, 22004663, 20590677, 30050558, 30547036, 30871348, 33019804, 19712804, 22466703) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Dilated cardiomyopathy 1DD Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 25, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 634 of the RBM20 protein (p.Arg634Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 19712804, 20590677, 33019804). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 269). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RBM20 protein function. Experimental studies have shown that this missense change affects RBM20 function (PMID: 22466703). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Sep 22, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Aug 14, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3,PP4. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2023

The p.R634Q variant (also known as c.1901G>A), located in coding exon 9 of the RBM20 gene, results from a G to A substitution at nucleotide position 1901. The arginine at codon 634 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in individuals with dilated cardiomyopathy and segregated with disease in multiple affected relatives in at least one family (Brauch KM et al. J. Am. Coll. Cardiol. 2009 Sep;54(10):930-42; Li D et al. Clin. Trans. Sci. 2010 Jun;3(3):90-7; Hey TM et al. Circ Heart Fail, 2019 03;12:e005700). In addition, other alterations affecting the same amino acid (p.R634W and p.R634L) have been reported in individuals with dilated cardiomyopathy and left ventricular non-compaction cardiomyopathy (Li D et al. Clin. Trans. Sci. 2010 Jun;3:90-7; Sedaghat-Hamedani F et al. Eur. Heart J., 2017 Dec;38:3449-3460). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Vest4		0.63
MutPred		0.70		Loss of MoRF binding (P = 0.0252);
MVP		0.88
ClinPred		0.86	D
GERP RS		5.7
gMVP		0.70

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

Other links and lift over

dbSNP: rs267607001; hg19: chr10-112572056; COSMIC: COSV65704238;