Submissions for variant NM_001134363.3(RBM20):c.1880+4_1880+6dup

dbSNP: rs397516597

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036950	SCV000060606	likely benign	not specified	2015-06-26	criteria provided, single submitter	clinical testing	c.1880+4_1880+6dup in intron 8 of RBM20: This variant is not expected to have cl inical significance because it does not alter the splice consensus sequence. It is present in 0.2% (19/8688) of European chromosomes by the Exome Aggregation Co nsortium (ExAC, http://exac.broadinstitute.org).
Illumina Laboratory Services, Illumina	RCV000271797	SCV000360357	uncertain significance	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000475809	SCV000562776	likely benign	Dilated cardiomyopathy 1DD	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618301	SCV000736522	likely benign	Cardiovascular phenotype	2018-05-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170925	SCV001333573	benign	Cardiomyopathy	2019-03-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036950	SCV001519490	benign	not specified	2021-03-01	criteria provided, single submitter	clinical testing	Variant summary: RBM20 c.1880+4_1880+6dupAGG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 156316 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 22 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.1880+4_1880+6dupAGG has been reported in the literature in sequencing studies reporting individuals affected with sporadic or familial Dialated Cardiomyopathy (example, Haas_2015). These report(s) 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=1; likely benign, n=3, benign, n=1). One submitter reports this variant as having co-occurred with another pathogenic variant that clearly explained the patient phenotype. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001529848	SCV001845289	likely benign	not provided	2021-01-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25163546)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000475809	SCV003920387	uncertain significance	Dilated cardiomyopathy 1DD	2021-03-30	criteria provided, single submitter	clinical testing	RBM20 NM_001134363.2 exon 8 c.1880+4_1880+6dup: This variant has been reported in the literature in at least one individual with DCM (Haas 2015 PMID:25163546). However, this variant is also present in 0.2% (177/75818) of European alleles in the Genome Aggregation Database, including 2 homozygotes (https://gnomad.broadinstitute.org/variant/10-112570222-T-TGAG) and is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:43978). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Although this variant occurs in the splice region, computational prediction tools do not suggest that it alters splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV001529848	SCV004699856	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	RBM20: BP4, BS1, BS2
Blueprint Genetics	RCV000157429	SCV000207173	likely benign	Primary familial hypertrophic cardiomyopathy	2014-07-21	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529848	SCV001744031	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036950	SCV001925962	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000036950	SCV001928990	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529848	SCV001966684	likely benign	not provided		no assertion criteria provided	clinical testing