Submissions for variant NM_001134363.3(RBM20):c.1881-3C>T

gnomAD frequency: 0.00575  dbSNP: rs138436392

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036951	SCV000060607	likely benign	not specified	2012-08-16	criteria provided, single submitter	clinical testing	c.1881-3C>T in intron 8 of RBM20: This variant is not expected to have clinical significance because it has been identified in 1.8% (25/1380) of African America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs138436392).
GeneDx	RCV000036951	SCV000171317	benign	not specified	2013-07-05	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.
Eurofins Ntd Llc (ga)	RCV000036951	SCV000233024	benign	not specified	2014-05-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232795	SCV000286185	benign	Dilated cardiomyopathy 1DD	2024-01-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000036951	SCV000306790	benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000248544	SCV000319105	benign	Cardiovascular phenotype	2015-07-27	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769263	SCV000900639	benign	Cardiomyopathy	2016-03-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000232795	SCV001159591	benign	Dilated cardiomyopathy 1DD	2023-09-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000232795	SCV001262180	likely benign	Dilated cardiomyopathy 1DD	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036951	SCV001338643	benign	not specified	2020-04-13	criteria provided, single submitter	clinical testing	Variant summary: RBM20 c.1881-3C>T alters a conserved 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 0.001 in 146224 control chromosomes, predominantly at a frequency of 0.019 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 760- 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 a benign polymorphism found primarily in populations of African or African-American origin. c.1881-3C>T has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Pugh_2014). 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. Four other 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. Based on the evidence outlined above, the variant was classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000232795	SCV000732917	benign	Dilated cardiomyopathy 1DD		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036951	SCV001920860	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000036951	SCV001970718	benign	not specified		no assertion criteria provided	clinical testing