ClinVar Genomic variation as it relates to human health
NM_001134363.3(RBM20):c.1901G>A (p.Arg634Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001134363.3(RBM20):c.1901G>A (p.Arg634Gln)
Variation ID: 269 Accession: VCV000000269.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q25.2 10: 110812298 (GRCh38) [ NCBI UCSC ] 10: 112572056 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 21, 2015 Feb 14, 2024 Dec 25, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001134363.3:c.1901G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001127835.2:p.Arg634Gln missense NC_000010.11:g.110812298G>A NC_000010.10:g.112572056G>A NG_021177.1:g.172902G>A LRG_382:g.172902G>A LRG_382t1:c.1901G>A - Protein change
- R634Q
- Other names
- p.R634Q:CGG>CAG
- Canonical SPDI
- NC_000010.11:110812297:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
RBM20 | - | - |
GRCh38 GRCh37 |
1816 | 1851 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 25, 2023 | RCV000000293.16 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 18, 2022 | RCV000183859.15 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 27, 2023 | RCV002408443.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Pathogenic
(Sep 22, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1DD
Affected status: yes
Allele origin:
de novo
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001439311.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
|
|
Pathogenic
(Aug 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1DD
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369495.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3,PP4.
|
|
Pathogenic
(Jan 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501812.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
Pathogenic
(Mar 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000236341.12
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
|
|
Pathogenic
(Oct 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1DD
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003835769.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
Likely pathogenic
(Apr 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002723692.2
First in ClinVar: Nov 29, 2022 Last updated: Jul 08, 2023 |
Comment:
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 … (more)
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, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
Pathogenic
(Dec 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1DD
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000286186.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
|
|
Pathogenic
(Jun 01, 2010)
|
no assertion criteria provided
Method: literature only
|
CARDIOMYOPATHY, DILATED, 1DD
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020437.2
First in ClinVar: Apr 04, 2013 Last updated: May 21, 2015 |
Comment on evidence:
In affected members of a large multigenerational family of Scottish ancestry ('DC-35') with dilated cardiomyopathy (CMD1DD; 613172), Brauch et al. (2009) identified heterozygosity for a … (more)
In affected members of a large multigenerational family of Scottish ancestry ('DC-35') with dilated cardiomyopathy (CMD1DD; 613172), Brauch et al. (2009) identified heterozygosity for a 1901G-A transition in exon 9 of the RBM20 gene, resulting in an arg634-to-gln (R634Q) substitution at a conserved residue in the RS domain. In a woman (Pedigree B) who was diagnosed with CMD at age 46 years and was negative for mutation in 14 known CMD-associated genes, Li et al. (2010) identified heterozygosity for a c.1959G-A transition (c.1959G-A, NM_001134363) in exon 9 of the RBM20 gene, resulting in the R634Q substitution. The mutation was not found in the dbSNP database or in DNA from 450 Caucasian controls. The patient died from decompensated heart failure 7 years after diagnosis. Li et al. (2010) noted that the CMD phenotype in the large Scottish family reported by Brauch et al. (2009) was aggressive, with onset at 18 years of age and 7 premature deaths, suggesting that the R634Q mutation is malignant whether present in sporadic or familial CMD. (less)
|
|
Pathogenic
(Apr 06, 2017)
|
no assertion criteria provided
Method: provider interpretation
|
not provided
Affected status: unknown
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924915.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
Comment:
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 … (more)
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 pregnancyâ€]). 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. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001744818.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919352.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928308.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951239.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
click to load more click to collapse |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Precise genomic editing of pathogenic mutations in RBM20 rescues dilated cardiomyopathy. | Nishiyama T | Science translational medicine | 2022 | PMID: 36417486 |
Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory. | Stava TT | European journal of preventive cardiology | 2022 | PMID: 35653365 |
Clinical and Genetic Investigations of 109 Index Patients With Dilated Cardiomyopathy and 445 of Their Relatives. | Hey TM | Circulation. Heart failure | 2020 | PMID: 33019804 |
Broad Genetic Testing in a Clinical Setting Uncovers a High Prevalence of Titin Loss-of-Function Variants in Very Early Onset Atrial Fibrillation. | Goodyer WR | Circulation. Genomic and precision medicine | 2019 | PMID: 31638414 |
Pathogenic RBM20-Variants Are Associated With a Severe Disease Expression in Male Patients With Dilated Cardiomyopathy. | Hey TM | Circulation. Heart failure | 2019 | PMID: 30871348 |
Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy. | Sedaghat-Hamedani F | European heart journal | 2017 | PMID: 29029073 |
RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. | Guo W | Nature medicine | 2012 | PMID: 22466703 |
Identification of novel mutations in RBM20 in patients with dilated cardiomyopathy. | Li D | Clinical and translational science | 2010 | PMID: 20590677 |
Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. | Brauch KM | Journal of the American College of Cardiology | 2009 | PMID: 19712804 |
Text-mined citations for rs267607001 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.