Submissions for variant NM_001134363.3(RBM20):c.3265C>G (p.Pro1089Ala)

gnomAD frequency: 0.00252  dbSNP: rs147356378

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036981	SCV000060637	uncertain significance	not specified	2012-05-01	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Pro1089Ala vari ant (RBM20) has not been reported in the literature nor previously identified by our laboratory. Proline (Pro) at position 1089 is not well conserved in evolut ion, suggesting that a change may be tolerated. Other computational analyses (bi ochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) a lso suggest that this variant may not impact the protein, though this informatio n is not predictive enough to rule out pathogenicity. Of note, the variant has b een identified in the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS). However, the data did not pass quality metrics and was therefore not i ncluded in the assessment of the variant. In summary, although this data support s that the Pro1089Ala variant may be benign, additional studies are needed to fu lly assess its clinical significance.
Eurofins Ntd Llc (ga)	RCV000036981	SCV000111390	benign	not specified	2015-08-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000036981	SCV000236367	benign	not specified	2016-10-14	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.
Ambry Genetics	RCV000252850	SCV000319867	likely benign	Cardiovascular phenotype	2019-01-25	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.
Invitae	RCV000467697	SCV000562792	benign	Dilated cardiomyopathy 1DD	2024-01-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000467697	SCV000611430	uncertain significance	Dilated cardiomyopathy 1DD	2017-05-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170931	SCV001333581	benign	Cardiomyopathy	2017-11-09	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000036981	SCV001433492	likely benign	not specified	2019-12-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036981	SCV001623205	benign	not specified	2021-04-26	criteria provided, single submitter	clinical testing	Variant summary: RBM20 c.3265C>G (p.Pro1089Ala) results in a non-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 0.00045 in 156498 control chromosomes, predominantly at a frequency of 0.0077 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 164 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 African or African-American origin. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=6, VUS n=1). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000467697	SCV004564923	likely benign	Dilated cardiomyopathy 1DD	2023-09-28	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036981	SCV001918922	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000036981	SCV001932369	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001727524	SCV001971873	likely benign	not provided		no assertion criteria provided	clinical testing