Submissions for variant NM_001134363.3(RBM20):c.3261_3262delinsG (p.Ser1087fs)

dbSNP: rs727504763

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156073	SCV000205786	likely pathogenic	Primary dilated cardiomyopathy	2017-03-23	criteria provided, single submitter	clinical testing	The p.Ser1087fs variant in RBM20 has been reported by our laboratory in 2 indivi duals with DCM and segregated with disease in 4 affected relatives from 1 family . This variant was absent from large population studies, though the ability of t hese studies to accurately detect indels may be limited. This variant is predict ed to cause a frameshift, which alters the protein?s amino acid sequence beginni ng at position 1087 and leads to a premature termination codon 17 amino acids do wnstream. This alteration is then predicted to lead to a truncated or absent pro tein. In summary, although additional studies are required to fully establish it s clinical significance, the p.Ser1087fs variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005208548	SCV000552904	uncertain significance	Dilated cardiomyopathy 1DD	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1087Argfs*17) in the RBM20 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in RBM20 cause disease. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with RBM20-related conditions. ClinVar contains an entry for this variant (Variation ID: 2691238). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000619175	SCV000736998	uncertain significance	Cardiovascular phenotype	2021-10-28	criteria provided, single submitter	clinical testing	The c.3261_3262delCCinsG variant, located in coding exon 11 of the RBM20 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.S1087Rfs*17). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of RBM20 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623790	SCV000740665	likely pathogenic	not provided	2017-02-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000623790	SCV001999547	uncertain significance	not provided	2019-08-30	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; The majority of RBM20 variants reported in HGMD in association with cardiomyopathy are missense variants (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 20590677, 19712804, 22004663)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486704	SCV004240018	uncertain significance	Cardiomyopathy	2023-01-12	criteria provided, single submitter	clinical testing