Submissions for variant NM_001134363.3(RBM20):c.1901G>A (p.Arg634Gln)

gnomAD frequency: 0.00001  dbSNP: rs267607001

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183859	SCV000236341	pathogenic	not provided	2022-03-18	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000293	SCV000286186	pathogenic	Dilated cardiomyopathy 1DD	2024-11-10	criteria provided, single submitter	clinical testing	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). Invitae Evidence 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 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000000293	SCV001369495	pathogenic	Dilated cardiomyopathy 1DD	2019-08-14	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3,PP4.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000000293	SCV001439311	pathogenic	Dilated cardiomyopathy 1DD	2020-09-22	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000183859	SCV002501812	pathogenic	not provided	2022-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408443	SCV002723692	likely pathogenic	Cardiovascular phenotype	2024-12-27	criteria provided, single submitter	clinical testing	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 variant was identified in one or more individuals with features consistent with dilated cardiomyopathy (DCM) and segregated with disease in at least one family (Brauch KM et al. J Am Coll Cardiol, 2009 Sep;54:930-41; Li D et al. Clin Transl Sci, 2010 Jun;3:90-7; Hey TM et al. Circ Heart Fail, 2020 Oct;13:e006701; Stava TT et al. Eur J Prev Cardiol, 2022 Oct;29:1789-1799; McGurk KA et al. Am J Hum Genet, 2023 Sep;110:1482-1495; Ambry internal data). 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.
Baylor Genetics	RCV000000293	SCV003835769	pathogenic	Dilated cardiomyopathy 1DD	2022-10-23	criteria provided, single submitter	clinical testing
OMIM	RCV000000293	SCV000020437	pathogenic	Dilated cardiomyopathy 1DD	2010-06-01	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000183859	SCV000924915	pathogenic	not provided	2017-04-06	no assertion criteria provided	provider interpretation	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 well as reduced penetrance. Of note, just a handful of reported affected individuals have atrial fibrillation. Li et al also suggested that their RBM20 cases were more severe than the rest of their cohort. However, it is important to note that neither group reported statistical analyses supporting these claims. Patrick Ellinor's group did run such an analysis and did not find worse outcomes, though, they did note that cases with RBM20 variants were more likely to have atrial fibrillation (Refaat et al 2012). p.Arg634Gln (c.1901G>A): p.Arg634Gln (c.1901G>A) has been seen in 3-4 unrelated cases of cardiomyopathy (in addition to this patient) with very strong segregation in one kindred. GeneDx notes they have seen it in one other individual with cardiomyopathy and that individual's unaffected sibling. This variant was actually one of the first variants reported with cardiomyopathy by Brauch et al (2009) in the initial study implicating RBM20 in familial cardiomyopathy. Nine affected family members, including quite distant relatives, carried the haplotype with the variant. Hershberger's group observed the variant in a seemingly sporadic case of DCM (Li et al 2010). The patient was diagnosed with DCM at 46yo and died of heart failure at 53yo. Family history was unrevealing, though family members were not available for study. We have seen this variant in two families in our center, including this patient's family. In one family the variant was seen in a 25yo with early onset atrial fibrillation and MRI that could be read as a normal variant or early signs of cardiomyopathy. Her brother had teenage onset atrial fibrillation and evidence of cardiomyopathy. In the other family it was found in a young adult with severe DCM onset in childhood whose father had atrial fibrillation onset at 19yo. We do not yet have records on the father but he reportedly has mitral valve prolapse with no mention of cardiomyopathy. The paternal grandfather died suddenly at 52yo. Per the GeneDx report: "Finally, mutations in the same residue (R634W) and in nearby residues (S635A, R636S, R636C, R636H) have been reported in the Human Gene Mutation Database in association with DCM (Stenson P et al., 2014)." A colleague has a family with p.Pro638Arg with cardiomyopathy, sudden death <18yo during exercise, atrial fibrillation, and young transplants. Other nearby variants include p.Pro638Leu, occurring in multiple families with haplotype analysis confirming they are not related (Brauch et al 2009). This is a nonconservative amino acid change, replacing a positively-charged Arginine with a polar Glutamine. The Arginine at this location is absolutely conserved across all ~100 vertebrate species for which we have information. Experimental studies have shown that this missense change is functionally inactive in a RBM20-dependent TTN splicing assay when compared to wild-type (PMID: 22466703; Guo et al. 2012). This variant lies within a previously described mutation rich region between residues 634 and 638. The majority of previously described disease causing variants in RBM20 are located in this region (PMID: 19712804 [Brauch et al. 2009], 2204663 [this paper does not seem relevant but cannot access it. Titled: “Successful mitral valve replacement for infective endocarditis in pregnancy”]). In summary, this variant is absent from controls, has been shown to segregate with dilated cardiomyopathy, has a deleterious effect on RBM20 activity, and is located in a well characterized mutation rich region. For these reasons, this variant has been classified as Pathogenic.” In total the variant has not been seen in 940 published controls: 480 individuals (Brauch et al 2009), 450 individuals (Li et al 2010). The variant was reported online in 1 of 73,476 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 11,909 individuals of Latino descent (as of April 4, 2017). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. This may be a low-quality site, since data from only 73,476 of more than 140,000 sequenced individuals is available.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000183859	SCV001744818	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000183859	SCV001919352	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000183859	SCV001928308	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000183859	SCV001951239	pathogenic	not provided		no assertion criteria provided	clinical testing