Submissions for variant NM_001134363.3(RBM20):c.2761A>G (p.Ile921Val)

gnomAD frequency: 0.00010  dbSNP: rs397516608

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036974	SCV000060630	uncertain significance	not specified	2012-11-26	criteria provided, single submitter	clinical testing	The Ile921Val variant in RBM20 has not been reported in the literature nor previ ously identified by our laboratory. This variant has also not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS), though this low fr equency is insufficient to assess the clinical significance of this variant. Com putational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional studies are needed to fully assess the clini cal significance of this variant.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201452	SCV000256197	uncertain significance	Cardiomyopathy		criteria provided, single submitter	clinical testing
GeneDx	RCV000766482	SCV000617105	uncertain significance	not provided	2023-11-02	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Invitae	RCV000647154	SCV000768941	likely benign	Dilated cardiomyopathy 1DD	2024-01-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000647154	SCV000894518	uncertain significance	Dilated cardiomyopathy 1DD	2021-09-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000201452	SCV001333577	uncertain significance	Cardiomyopathy	2021-06-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766482	SCV004698995	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036974	SCV004803452	likely benign	not specified	2024-01-16	criteria provided, single submitter	clinical testing	Variant summary: RBM20 c.2761A>G (p.Ile921Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.4e-05 in 188006 control chromosomes, predominantly at a frequency of 0.00016 within the Non-Finnish European subpopulation in the gnomAD database (v4.0.0). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 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.2761A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 43999). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV004018825	SCV004938867	uncertain significance	Cardiovascular phenotype	2021-04-12	criteria provided, single submitter	clinical testing	The c.2761A>G (p.I921V) alteration is located in exon 11 (coding exon 11) of the RBM20 gene. This alteration results from a A to G substitution at nucleotide position 2761, causing the isoleucine (I) at amino acid position 921 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.