ClinVar Genomic variation as it relates to human health
NM_001134363.3(RBM20):c.2737G>A (p.Glu913Lys)
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.2737G>A (p.Glu913Lys)
Variation ID: 43998 Accession: VCV000043998.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q25.2 10: 110821356 (GRCh38) [ NCBI UCSC ] 10: 112581114 (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 Dec 19, 2017 Apr 20, 2024 Jan 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001134363.3:c.2737G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001127835.2:p.Glu913Lys missense NC_000010.11:g.110821356G>A NC_000010.10:g.112581114G>A NG_021177.1:g.181960G>A LRG_382:g.181960G>A LRG_382t1:c.2737G>A - Protein change
- E913K
- Other names
- p.E913K:GAG>AAG
- Canonical SPDI
- NC_000010.11:110821355:G: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
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
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 7, 2023 | RCV000036973.10 | |
Pathogenic (2) |
criteria provided, single submitter
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Feb 17, 2023 | RCV000497300.6 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 13, 2024 | RCV000647156.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 23, 2017 | RCV000769275.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 12, 2021 | RCV002433499.1 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV002054621.1 |
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
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
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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 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000900651.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019 |
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Pathogenic
(May 12, 2021)
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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: SCV002747477.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.E913K pathogenic mutation (also known as c.2737G>A), located in coding exon 11 of the RBM20 gene, results from a G to A substitution at … (more)
The p.E913K pathogenic mutation (also known as c.2737G>A), located in coding exon 11 of the RBM20 gene, results from a G to A substitution at nucleotide position 2737. The glutamic acid at codon 913 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in individuals with dilated cardiomyopathy (DCM) and has shown co-segregation with disease in several families, including one with at least nine affected members (Beqqali A et al. Cardiovasc Res, 2016 10;112:452-63; Invitae pers. comm.). This alteration was reported in one individual with DCM from a genetic testing cohort, who also had variants in other cardiac-related genes (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8;Walsh R et al. Genet Med, 2017 02;19:192-203). Functional studies suggested this variant destabilizes the protein and may impact splicing in TTN; however, the mechanism of disease for RBM20 has not been well-established (Khan MA et al. Circ Res, 2016 Oct;119:996-1003; Beqqali A et al. Cardiovasc Res, 2016 10;112:452-63). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1DD
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768085.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy, 1DD (MIM#613172). While some publications suggest a dominant negative mechanism for variants in the hotspot affecting residues between 630 and 640 (PMID: 32187365, PMID: 29895960), this has been recently disproven (PMID: 32840935). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated glutamic acid-rich region (PMID: 30547036, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in at least five unrelated individuals with dilated cardiomyopathy (DCM) (ClinVar, PMID: 27496873, PMID: 30547036). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate in at least one family with eight affected individuals with DCM (PMID: 27496873). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Studies with both an affected individual’s heart cells and cell lines have showed that this variant strongly decreases protein levels. In addition, it alters TTN gene splicing and protein isoform composition, leading to an increase in the larger titin isoform (PMID: 27496873). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) (less)
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Pathogenic
(Jan 13, 2024)
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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: SCV000768943.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 913 of the RBM20 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 913 of the RBM20 protein (p.Glu913Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (DCM) (PMID: 24503780, 27496873; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43998). 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) performed at Invitae indicates that this missense variant is not expected to disrupt RBM20 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects RBM20 function (PMID: 27496873). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Left ventricular noncompaction cardiomyopathy
Affected status: yes
Allele origin:
germline
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Klaassen Lab, Charite University Medicine Berlin
Accession: SCV002495732.1
First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022 |
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Pathogenic
(Feb 17, 2023)
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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: SCV000236360.14
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 demonstrate that E913K results in reduced RBM20 protein expression, which alters titin … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that E913K results in reduced RBM20 protein expression, which alters titin splicing in the heart (Beqqali et al., 2016; Khan et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27496873, 27531932, 24503780, 27532257, 29304022, 28941705, 30050558, 30871348, 30871351, 26582918, 35288587, 33019804, 34540771) (less)
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Pathogenic
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812463.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in RBM20 is predicted to replace glutamic acid with lysine at codon 913, p.(Glu913Lys). The glutamic acid residue is highly conserved (100 … (more)
This sequence change in RBM20 is predicted to replace glutamic acid with lysine at codon 913, p.(Glu913Lys). The glutamic acid residue is highly conserved (100 vertebrates, UCSC), and is located in a glutamic acid-rich region (PMID: 27496873). There is a small physicochemical difference between glutamic acid and lysine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in multiple individuals with RBM20-related cardiomyopathy, including dilated cardiomyopathy (DCM), noncompaction cardiomyopathy, or left ventricular noncompaction cardiomyopathy (PMID: 27532257, 29447731, 34540771, 35113650; ClinVar: SCV000924914.1, SCV000060629.7, SCV000768943.6). The variant has been reported to segregate with DCM over three generations in a single family (PMID: 27496873). At least one individual with this variant displayed downregulation of RBM20 protein in heart tissue compared to controls and TTN RNA mis-splicing causing a significant shift from the less compliant toward the highly compliant TTN isoforms (PMID: 27496873). Reduced RBM20 protein expression was also demonstrated in an in vitro cell line assay indicating that this variant impacts protein function (PMID: 27496873). Computational evidence is uninformative for the missense substitution (REVEL = 0.54). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Moderate, PP4_Moderate, PM2_Supporting, PS3_Supporting. (less)
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Likely Pathogenic
(Dec 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060629.8
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The p.Glu913Lys variant in RBM20 has been reported in 3 individuals with dilated cardiomyopathy (DCM) and segregated with disease in at least 9 affected relatives … (more)
The p.Glu913Lys variant in RBM20 has been reported in 3 individuals with dilated cardiomyopathy (DCM) and segregated with disease in at least 9 affected relatives from 2 families (Beqqali 2016 PMID 27496873, Walsh 2017 PMID 27532257, van den Hoogenhof 2018 PMID 29650543, Hey 2019 PMID 30871348, Parikh 2019 PMID 30871351, LMM Data). This variant has also been reported by other clinical laboratories in ClinVar (Variant ID: 43998) but is absent from large population studies. RNA sequencing and RT-PCR performed on heart tissue from a patient harboring this variant as well as in vitro studies using transfected cells suggest that this variant affects RBM20 protein function (Beqqali 2016 PMID 27496873, Khan 2016 PMID 27531932, van den Hoogenhof 2018 PMID 29650543). Computational prediction tools and conservation analysis suggest are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP criteria applied: PS4_Supporting, PP1_Strong, PM2_Supporting, PS3_Moderate, PP3. (less)
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Likely pathogenic
(Jun 09, 2017)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924914.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
Comment:
Our patient is a 13 year-old male listed for heart tranplant due to familial DCM. He had a Comprehensive Cardiomyopathy Panel with the GeneDx laboratory … (more)
Our patient is a 13 year-old male listed for heart tranplant due to familial DCM. He had a Comprehensive Cardiomyopathy Panel with the GeneDx laboratory which included sequencing of 76 genes and additional deletion/duplication analysis of 61 of those genes (nuclear genes) associated with various forms of cardiomyopathy: ABCC9 , ACTC (ACTC1), ACTN2, ANKRD1, BAG3 , BRAF, CAV3, CRYAB , CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, [no sequence data could be obtained for MYH6], MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL , NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. Results show that one variant was detected: p.Glu913Lys (E913K; c.2737G>A) in exon 11 of the RBM20 gene. Based on the information reviewed below, including very strong segregation data in a family with DCM, we classify p.Glu913Lys as Likely Pathogenic. This variant has been reported in the literature by Beqqali et al. (2016) in a family with DCM. It segregated with disease in 9 affected family members, which would happen by chance in 1/256 or 0.4% of cases. No other disease-causing variants were found in 83 DCM genes including TTN. The index patient presented with heart failure at age 35. His brother was diagnosed at age 19 and died of heart failure at age 29, His mother died of heart failure at age 72. Upon family-member screening, other family members were diagnosed with DCM at ages 12-17, and one of them underwent heart transplant at age 19. This paper also contains in vitro data on the variant. The authors report that it leads to lower RBM20 protein levels by affecting protein stability. This then causes altered splicing of titin (TTN) in the cardiomyocytes, resulting in a shift from the more stiff N2B isoform to the more compliant titin isoform N2BA, an increased sarcomere resting length, and decreased length-dependent activation (impaired Frank-Starling mechanism). In a separate paper (Khan et al. 2016), this same group shows the variant to alter formation of circular RNAs from TTN. This variant in RBM20 has been identified by LMM laboratory in 2 adults with DCM, according to their submission to ClinVar, for a total of 4 DCM families known to have it, including our patient's. It is absent from the gnomAD population database of 140,000 individuals. However, there is poor sequencing coverage at this location with only 65% of samples covered at 1x, much less 20x. This is a nonconservative amino acid change, resulting in the replacement of a negatively charged Glutamic Acid with a positively charged Lysine. Glutamic Acid at this location is absolutely conserved across ~100 vertebrate species for which we have data. The adjacent residues are also highly conserved. While pathogenic variants in RBM20 have been reported in cases of DCM within exon 9 (Brauch 2009, Li 2010), the impact of variants in other regions of the gene is currently unclear. However, a nearby variant, p.Glu916Lys, is listed as Likely Pathogenic by LMM in ClinVar, as it was found to segregate with disease in 5 affected individuals, including 4 obligate carriers. Variants in the RBM20 gene have been reported in approximately 3% of patients with DCM (Refaat et al., 2012), but specifically in pediatric patients may represent a higher proportion: Pugh et al. (2014) found high-confidence RBM20 variants in over 6% of pediatric patients with DCM. Variants in RBM20 are relatively newly reported with cardiomyopathy, so only minimal data on disease-associated variation in this gene is available. Currently, only 16 Likely Pathogenic or Pathogenic variants in this gene are listed in ClinVar (as of June 2017). (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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Pregnancy Outcomes in Females With Dilated Cardiomyopathy-Associated Rare Genetic Variants. | Peters S | Circulation. Genomic and precision medicine | 2022 | PMID: 35113650 |
Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pediatric and Adult Left Ventricular Noncompaction Cardiomyopathy. | Schultze-Berndt A | Frontiers in pediatrics | 2021 | PMID: 34540771 |
Circular RNAs: Functions and Clinical Significance in Cardiovascular Disease. | Zhang L | Frontiers in cell and developmental biology | 2020 | PMID: 33134301 |
Cardiomyopathy-associated mutations in the RS domain affect nuclear localization of RBM20. | Gaertner A | Human mutation | 2020 | PMID: 32840935 |
Structural basis of UCUU RNA motif recognition by splicing factor RBM20. | Upadhyay SK | Nucleic acids research | 2020 | PMID: 32187365 |
Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy. | Parikh VN | Circulation. Heart failure | 2019 | PMID: 30871351 |
Pathogenic RBM20-Variants Are Associated With a Severe Disease Expression in Male Patients With Dilated Cardiomyopathy. | Hey TM | Circulation. Heart failure | 2019 | PMID: 30871348 |
Alternative Splicing Regulator RBM20 and Cardiomyopathy. | Watanabe T | Frontiers in molecular biosciences | 2018 | PMID: 30547036 |
Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization. | Murayama R | Scientific reports | 2018 | PMID: 29895960 |
RBM20 Mutations Induce an Arrhythmogenic Dilated Cardiomyopathy Related to Disturbed Calcium Handling. | van den Hoogenhof MMG | Circulation | 2018 | PMID: 29650543 |
Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy. | van Waning JI | Journal of the American College of Cardiology | 2018 | PMID: 29447731 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
RBM20 Regulates Circular RNA Production From the Titin Gene. | Khan MA | Circulation research | 2016 | PMID: 27531932 |
A mutation in the glutamate-rich region of RNA-binding motif protein 20 causes dilated cardiomyopathy through missplicing of titin and impaired Frank-Starling mechanism. | Beqqali A | Cardiovascular research | 2016 | PMID: 27496873 |
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 |
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Text-mined citations for rs397516607 ...
HelpRecord last updated Apr 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.