Submissions for variant NM_001134363.3(RBM20):c.2042A>G (p.Tyr681Cys)

gnomAD frequency: 0.00016  dbSNP: rs372048968

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481759	SCV000565482	uncertain significance	not provided	2025-04-10	criteria provided, single submitter	clinical testing	Reported in association with sudden unexplained death and dilated cardiomyopathy; however, additional variants in cardiac-related genes were identified in some individuals (PMID: 29517769, 26272908, 29650543, 31737537); Identified in an abstract by Dabbagh in a patient with inflammation of the left ventricle, MVP, atrial fibrillation, NSVT, and PVCs (Dabbagh et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26272908, 29650543, 31737537, 33671899, Dabbagh2022[abstract], 36367695, 37652022, 30847666, 29517769)
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000515711	SCV000611780	uncertain significance	Dilated cardiomyopathy 1DD	2017-08-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000515711	SCV000648361	likely benign	Dilated cardiomyopathy 1DD	2024-12-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620460	SCV000736555	uncertain significance	Cardiovascular phenotype	2025-01-31	criteria provided, single submitter	clinical testing	The p.Y681C variant (also known as c.2042A>G), located in coding exon 9 of the RBM20 gene, results from an A to G substitution at nucleotide position 2042. The tyrosine at codon 681 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a sudden infant death cohort and in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Santori M et al. Arch Dis Child. 2015;100:952-6; van den Hoogenhof MMG. Circulation. 2018;138:1330-1342). This variant has also been detected in a pediatric DCM cohort where, in one individual, it co-occurred with a variant in another cardiomyopathy-related gene (Herkert JC et al. Genet. Med., 2018 11;20:1374-1386). This variant was also detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant has also been reported in an arrhythmogenic disorders and a dilated cardiomyopathy (DCM) cohort (Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; McGurk KA et al. Am J Hum Genet, 2023 Sep;110:1482-1495). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798854	SCV002042298	uncertain significance	Cardiomyopathy	2019-05-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515711	SCV002792837	uncertain significance	Dilated cardiomyopathy 1DD	2021-07-26	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000515711	SCV005912370	uncertain significance	Dilated cardiomyopathy 1DD	2022-09-27	criteria provided, single submitter	research
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000620460	SCV006065669	uncertain significance	Cardiovascular phenotype	2025-04-09	criteria provided, single submitter	clinical testing