Submissions for variant NM_001134363.3(RBM20):c.3452-10C>T

gnomAD frequency: 0.00369  dbSNP: rs60618533

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036986	SCV000060642	benign	not specified	2015-03-11	criteria provided, single submitter	clinical testing	3452-10C>T in intron 12 of RBM20: This variant is not expected to have clinical significance because it has been identified in 1.1% (23/2144) of African America n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs60618533).
GeneDx	RCV000036986	SCV000236323	benign	not specified	2014-08-03	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230014	SCV000286204	benign	Dilated cardiomyopathy 1DD	2025-02-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000230014	SCV000360373	uncertain significance	Dilated cardiomyopathy 1DD	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770285	SCV000901717	benign	Cardiomyopathy	2016-07-27	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852635	SCV000995340	benign	Hypertrophic cardiomyopathy	2019-06-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036986	SCV001337941	benign	not specified	2020-01-13	criteria provided, single submitter	clinical testing	Variant summary: RBM20 c.3452-10C>T alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 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 184560 control chromosomes, predominantly at a frequency of 0.011 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 440 fold of 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. To our knowledge, no occurrence of c.3452-10C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (4x) or VUS (1x). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000230014	SCV001471870	benign	Dilated cardiomyopathy 1DD	2022-02-08	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036986	SCV001921275	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000036986	SCV001967061	benign	not specified		no assertion criteria provided	clinical testing