ClinVar Genomic variation as it relates to human health
NM_001134363.3(RBM20):c.1906C>A (p.Arg636Ser)
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
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NM_001134363.3(RBM20):c.1906C>A (p.Arg636Ser)
Variation ID: 270 Accession: VCV000000270.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q25.2 10: 110812303 (GRCh38) [ NCBI UCSC ] 10: 112572061 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 Feb 28, 2024 Oct 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001134363.3:c.1906C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001127835.2:p.Arg636Ser missense NC_000010.11:g.110812303C>A NC_000010.10:g.112572061C>A NG_021177.1:g.172907C>A LRG_382:g.172907C>A LRG_382t1:c.1906C>A - Protein change
- R636S
- Other names
- p.R636S:CGT>AGT
- Canonical SPDI
- NC_000010.11:110812302:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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RBM20 | - | - |
GRCh38 GRCh37 |
1816 | 1851 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
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Oct 17, 2023 | RCV000000294.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 6, 2022 | RCV000183860.6 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2016 | RCV000208477.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 1, 2023 | RCV003338375.1 |
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
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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
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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
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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. |
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Likely pathogenic
(Oct 31, 2016)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060608.6
First in ClinVar: May 03, 2013 Last updated: May 03, 2018 |
Comment:
The p.Arg636Ser variant in RBM20 has been reported in 3 individuals with DCM, se gregated with disease in 6 affected relatives from 2 families, and … (more)
The p.Arg636Ser variant in RBM20 has been reported in 3 individuals with DCM, se gregated with disease in 6 affected relatives from 2 families, and was absent fr om 960 race-matched control chromosomes (Brauch 2009). In addition, this variant has been identified by our laboratory in 1 individual with DCM and 1 individual with LVNC. In vitro functional studies provide some evidence that the p.Arg636S er variant may impact protein function (Guo 2012, Wyles 2016). However, these ty pes of assays may not accurately represent biological function. Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In addition, this variant lies within exon 9, which encodes a conserved protein domain where other pathogenic variants have been reported (Brauch 2009, Li 2010). Lastly, a different disease-causing substitution has been reported at this position (p.Arg636His; Brauch 2009, Li 2010, Wells 2013, LMM data) suggesti ng that changes at this position may not be tolerated. In summary, although addi tional studies are required to fully establish its clinical significance, the p. Arg636Ser variant is likely pathogenic. (less)
Number of individuals with the variant: 5
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Pathogenic
(Oct 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1DD
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000552913.10
First in ClinVar: May 29, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 636 of the RBM20 protein (p.Arg636Ser). … (more)
This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 636 of the RBM20 protein (p.Arg636Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 19712804, 26604136; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 270). 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). This variant disrupts the p.Arg636 amino acid residue in RBM20. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19712804, 20590677, 21483645, 23861363, 24503780, 26084686). 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. (less)
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Pathogenic
(Apr 10, 2015)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000264171.2
First in ClinVar: Mar 01, 2016 Last updated: May 03, 2018 |
Number of individuals with the variant: 2
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Pathogenic
(Jan 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000236342.14
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies showed that the hiPSC-CMs harboring the R636S variant were less capable of … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies showed that the hiPSC-CMs harboring the R636S variant were less capable of maintaining their sarcomeric structure, demonstrated defective Ca2+ handling, and were more susceptible to positive chronotropic (heart rate) stress (Wyles et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 270); This variant is associated with the following publications: (PMID: 27363581, 22466703, 19712804, 27496873, 30871348, 30871351, 29343803, 21483645, 33019804, 34732726, 33671899, 34575212, 33188278, 34333030, 26604136) (less)
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Pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004058314.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The p.R636S pathogenic mutation (also known as c.1906C>A), located in coding exon 9 of the RBM20 gene, results from a C to A substitution at … (more)
The p.R636S pathogenic mutation (also known as c.1906C>A), located in coding exon 9 of the RBM20 gene, results from a C to A substitution at nucleotide position 1906. The arginine at codon 636 is replaced by serine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals with dilated cardiomyopathy (DCM) and has been shown to segregate with DCM across several families, some of which exhibited reduced penetrance (Brauch KM et al. J Am Coll Cardiol. 2009;54:930-41; Broendberg AK et al. Eur J Hum Genet. 2018 Mar;26(3):303-313; Hey TM et al. Circ Heart Fail. 2019 Mar;12(3):e005700; Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799). Functional studies have indicated that this variant adversely impacts protein function (Guo W et al. Nat Med. 2012;18:766-73; Wyles SP et al. Hum Mol Genet. 2016;25:254-65). Other alterations at the same codon, p.R636C (c.1906C>T) and p.R636H (c.1907G>A), have also been reported in association with DCM (Li D et al. Clin Transl Sci. 2010;3:90-7). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Sep 01, 2009)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, DILATED, 1DD
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020438.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members of 3 large multigenerational families with dilated cardiomyopathy (CMD1DD; 613172), 2 of Norwegian ancestry ('DC-9' and 'DC-27') and 1 of German ancestry … (more)
In affected members of 3 large multigenerational families with dilated cardiomyopathy (CMD1DD; 613172), 2 of Norwegian ancestry ('DC-9' and 'DC-27') and 1 of German ancestry ('DC-46'), Brauch et al. (2009) identified heterozygosity for a 1906C-A transversion in exon 9 of the RBM20 gene, resulting in an arg636-to-ser (R636S) substitution at a conserved residue in the RS domain. (less)
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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 |
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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 |
Pathogenic RBM20-Variants Are Associated With a Severe Disease Expression in Male Patients With Dilated Cardiomyopathy. | Hey TM | Circulation. Heart failure | 2019 | PMID: 30871348 |
Targeted next generation sequencing in a young population with suspected inherited malignant cardiac arrhythmias. | Broendberg AK | European journal of human genetics : EJHG | 2018 | PMID: 29343803 |
Pharmacological Modulation of Calcium Homeostasis in Familial Dilated Cardiomyopathy: An In Vitro Analysis From an RBM20 Patient-Derived iPSC Model. | Wyles SP | Clinical and translational science | 2016 | PMID: 27105042 |
Modeling structural and functional deficiencies of RBM20 familial dilated cardiomyopathy using human induced pluripotent stem cells. | Wyles SP | Human molecular genetics | 2016 | PMID: 26604136 |
Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy. | Akinrinade O | European heart journal | 2015 | PMID: 26084686 |
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. | Pugh TJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24503780 |
Whole exome sequencing identifies a causal RBM20 mutation in a large pedigree with familial dilated cardiomyopathy. | Wells QS | Circulation. Cardiovascular genetics | 2013 | PMID: 23861363 |
King of hearts: a splicing factor rules cardiac proteins. | Linke WA | Nature medicine | 2012 | PMID: 22561820 |
RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. | Guo W | Nature medicine | 2012 | PMID: 22466703 |
Genetic variation in the alternative splicing regulator RBM20 is associated with dilated cardiomyopathy. | Refaat MM | Heart rhythm | 2012 | PMID: 22004663 |
Rare variant mutations identified in pediatric patients with dilated cardiomyopathy. | Rampersaud E | Progress in pediatric cardiology | 2011 | PMID: 21483645 |
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 |
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Text-mined citations for rs267607002 ...
HelpRecord last updated Apr 06, 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.