ClinVar Miner

Submissions for variant NM_001134363.3(RBM20):c.3265C>G (p.Pro1089Ala) (rs147356378)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 ( 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000467697 SCV000562792 benign Dilated cardiomyopathy 1DD 2020-11-30 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.

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