ClinVar Miner

Submissions for variant NM_001134363.3(RBM20):c.2662G>A (p.Asp888Asn) (rs201370621)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036970 SCV000060626 benign not specified 2015-02-04 criteria provided, single submitter clinical testing p.Asp888Asn in exon 11 of RBM20: This variant is not expected to have clinical s ignificance because it has been identified in 2% (32/1592) of Finnish chromosome s by the Exome Aggregation Consortium (ExAC,; dbS NP rs201370621).
Blueprint Genetics RCV000036970 SCV000207180 benign not specified 2015-02-17 criteria provided, single submitter clinical testing
GeneDx RCV000036970 SCV000236357 benign not specified 2016-08-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CSER _CC_NCGL, University of Washington RCV000210896 SCV000264611 likely benign Primary dilated cardiomyopathy 2015-12-01 criteria provided, single submitter research
Invitae RCV000228639 SCV000286195 likely benign Dilated cardiomyopathy 1DD 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617547 SCV000735288 benign Cardiovascular phenotype 2015-06-11 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;in silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000036970 SCV000740667 likely benign not specified 2017-04-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000228639 SCV000886043 benign Dilated cardiomyopathy 1DD 2020-06-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769273 SCV000900649 benign Cardiomyopathy 2017-04-20 criteria provided, single submitter clinical testing
Baylor-Hopkins Center for Mendelian Genomics,Johns Hopkins University RCV000228639 SCV000924180 uncertain significance Dilated cardiomyopathy 1DD criteria provided, single submitter research
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852632 SCV000995337 likely benign Primary dilated cardiomyopathy; Cardiomyopathy 2019-05-28 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000853424 SCV000996335 benign Hypertrophic cardiomyopathy; Cardiac arrest 2017-03-17 criteria provided, single submitter research This RBM20 Asp888Asn variant has previously been reported in DCM patients (Pugh TJ, et al., 2014; Refaat MM, et al., 2012) and is present in the large Exome Aggregation Consortium dataset ( at a minor allele frequency of 0.003 (European-Finnish subpopulation frequency is 0.02) which is much higher than expected for DCM (Nouhravesh N, et al., 2016) or any other inherited heart condition. Aspartic acid (Asp) at position 888 is only moderately conserved across mammals (not conserved in distantly related species). In silico tools SIFT, MutationTaster and PolyPhen-2 predict RBM20 Asp888Asn to have a possible damaging effect. Patients identified by our laboratory with the RBM20 Asp888Asn variant had different phenotypes: 1 HCM case, 1 patient who had a resuscitated cardiac arrest event, and 1 sudden unexplained death in epilepsy (SUDEP) case. In summary, based on the frequency of this variant in ~0.3% of the general population, and in 3 unrelated cases with varying disease manifestations in our data, we do not expect this variant to cause disease in isolation. In summary, we classify this variant as "benign".
Mendelics RCV000228639 SCV001138171 benign Dilated cardiomyopathy 1DD 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000036970 SCV001478785 likely benign not specified 2021-01-14 criteria provided, single submitter clinical testing Variant summary: RBM20 c.2662G>A (p.Asp888Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0039 in 155726 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 82.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is benign. c.2662G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy, without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000036970 SCV000280433 uncertain significance not specified 2014-10-07 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asp888Asn (c.2662 G>A) in RBM20 (NM_001134363.1) Based on failure to segregate, presence in a general population sample, and co-occurrence of other pathogenic variants in a subset of cases, we consider this variant to be a variant of uncertain significance, likely benign. It is also possible that it plays a role as a modifer though there is insufficient data available to assess that. 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. 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. The variant has been seen in at least 6 unrelated cases of DCM (not including this patient) and a case of pediatric restrictive cardiomyopathy. However in one unpublished family the variant did no co-segregate with DCM. Refaat et al (2012) reported the variant in a female with DCM and atrial fibrillation. They observed RBM20 variants in 3% of the 283 patients with non-ischemic DCM studied. Patients were recruited from the US and were participants in the Genetic Risk Assessment of Defibrillator Events (GRADE) study. Per the GeneDx report the LMM has a family with this variant and DCM where the variant failed to segregate with disease. Per the LMM's ClinVar submission (SCV000060626, last reviewed by LMM January 2013), they have seen the variant in 4 individuals with clinical features of DCM, one of whom has a likely pathogenic variant in another gene. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging while SIFT predicts it to be tolerated. In total the variant has been seen in 3 of 3034 published controls and individuals from publicly available population datasets. However, the variant is listed in dbSNP with data from the exome chip and ClinSeq (rs201370621). Population frequency data in dbSNP from ClinSeq notes that 3 of ~284 individuals were heterozygous for this variant. There is no variation at codon 888 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~2750 Caucasian and African American individuals (as of March 8th, 2013). The variant was not observed in the following published control samples: 600 (Refaat et al 2012).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000228639 SCV000732924 likely benign Dilated cardiomyopathy 1DD no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001573531 SCV001799538 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000036970 SCV001922006 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000036970 SCV001927291 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000036970 SCV001958402 benign not specified no assertion criteria provided clinical testing

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