Submissions for variant NM_001134363.3(RBM20):c.2452G>T (p.Ala818Ser)

gnomAD frequency: 0.00024  dbSNP: rs200271618

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036965	SCV000060621	uncertain significance	not specified	2015-02-20	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000036965	SCV000236315	likely benign	not specified	2015-07-09	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	RCV001083431	SCV000552931	likely benign	Dilated cardiomyopathy 1DD	2025-01-29	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845312	SCV000987354	uncertain significance	not provided		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000845312	SCV001148093	likely benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	RBM20: BP4
Illumina Laboratory Services, Illumina	RCV001083431	SCV001265838	uncertain significance	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170927	SCV001333575	benign	Cardiomyopathy	2018-07-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036965	SCV001426805	likely benign	not specified	2020-07-20	criteria provided, single submitter	clinical testing	Variant summary: RBM20 c.2452G>T (p.Ala818Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 123062 control chromosomes, predominantly at a frequency of 0.00056 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 11.95 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2452G>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign n=4, VUS n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002444475	SCV002732102	likely benign	Cardiovascular phenotype	2018-11-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.