Submissions for variant NM_001134363.3(RBM20):c.3373G>A (p.Glu1125Lys)

gnomAD frequency: 0.00333  dbSNP: rs116908219

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036984	SCV000060640	benign	not specified	2017-08-10	criteria provided, single submitter	clinical testing	p.Glu1125Lys in exon 12 of RBM20: This variant is classified as benign because i t has been identified in 1.8% (157/8538) of Ashkenazi Jewish chromosomes, includ ing 4 homozygotes by the Genome Aggregation Database (gnomAD, http://gmomad.broa dinstitute.org; dbSNP rs116908219).
GeneDx	RCV000036984	SCV000236322	benign	not specified	2018-01-10	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.
Invitae	RCV000226115	SCV000286203	benign	Dilated cardiomyopathy 1DD	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000252174	SCV000318433	benign	Cardiovascular phenotype	2018-06-25	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000036984	SCV000740658	likely benign	not specified	2016-05-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770284	SCV000901716	likely benign	Cardiomyopathy	2017-08-18	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852634	SCV000995339	benign	Arrhythmogenic right ventricular cardiomyopathy; Long QT syndrome	2019-03-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000226115	SCV001138172	likely benign	Dilated cardiomyopathy 1DD	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000857871	SCV001148099	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	RBM20: BP4, BS1
Illumina Laboratory Services, Illumina	RCV000226115	SCV001262292	likely benign	Dilated cardiomyopathy 1DD	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036984	SCV001339224	benign	not specified	2020-03-30	criteria provided, single submitter	clinical testing	Variant summary: RBM20 c.3373G>A (p.Glu1125Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 156520 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 145-fold the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.3373G>A has been reported in the literature in individuals affected with Cardiomyopathy without strong evidence for causality (examples- Lopes_2013, Pugh_2014, Bottillo_2016, Jaaskelainen_2019). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They have cited the variant as benign (n=4), likely benign (n=4) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000226115	SCV000732928	likely benign	Dilated cardiomyopathy 1DD		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036984	SCV001924511	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000857871	SCV001932254	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000036984	SCV001955670	benign	not specified		no assertion criteria provided	clinical testing