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

gnomAD frequency: 0.00344  dbSNP: rs201370621

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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, http://exac.broadinstitute.org; 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	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617547	SCV000735288	benign	Cardiovascular phenotype	2015-06-11	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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	2023-08-24	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 School of Medicine	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 (http://exac.broadinstitute.org/) 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.
CeGaT Center for Human Genetics Tuebingen	RCV001573531	SCV003916642	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	RBM20: BS1
PreventionGenetics, part of Exact Sciences	RCV003924914	SCV004741625	likely benign	RBM20-related disorder	2019-03-18	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000036970	SCV001958402	benign	not specified		no assertion criteria provided	clinical testing