Submissions for variant NM_001134363.3(RBM20):c.1906C>A (p.Arg636Ser)

dbSNP: rs267607002

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000208477	SCV000060608	likely pathogenic	Primary dilated cardiomyopathy	2016-10-31	criteria provided, single submitter	clinical testing	The p.Arg636Ser variant in RBM20 has been reported in 3 individuals with DCM, se gregated with disease in 6 affected relatives from 2 families, and was absent fr om 960 race-matched control chromosomes (Brauch 2009). In addition, this variant has been identified by our laboratory in 1 individual with DCM and 1 individual with LVNC. In vitro functional studies provide some evidence that the p.Arg636S er variant may impact protein function (Guo 2012, Wyles 2016). However, these ty pes of assays may not accurately represent biological function. Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In addition, this variant lies within exon 9, which encodes a conserved protein domain where other pathogenic variants have been reported (Brauch 2009, Li 2010). Lastly, a different disease-causing substitution has been reported at this position (p.Arg636His; Brauch 2009, Li 2010, Wells 2013, LMM data) suggesti ng that changes at this position may not be tolerated. In summary, although addi tional studies are required to fully establish its clinical significance, the p. Arg636Ser variant is likely pathogenic.
GeneDx	RCV000183860	SCV000236342	pathogenic	not provided	2022-01-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies showed that the hiPSC-CMs harboring the R636S variant were less capable of maintaining their sarcomeric structure, demonstrated defective Ca2+ handling, and were more susceptible to positive chronotropic (heart rate) stress (Wyles et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 270); This variant is associated with the following publications: (PMID: 27363581, 22466703, 19712804, 27496873, 30871348, 30871351, 29343803, 21483645, 33019804, 34732726, 33671899, 34575212, 33188278, 34333030, 26604136)
Blueprint Genetics	RCV000208477	SCV000264171	pathogenic	Primary dilated cardiomyopathy	2015-04-10	criteria provided, single submitter	clinical testing
Invitae	RCV000000294	SCV000552913	pathogenic	Dilated cardiomyopathy 1DD	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 636 of the RBM20 protein (p.Arg636Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 19712804, 26604136; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 270). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RBM20 protein function. Experimental studies have shown that this missense change affects RBM20 function (PMID: 22466703). This variant disrupts the p.Arg636 amino acid residue in RBM20. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19712804, 20590677, 21483645, 23861363, 24503780, 26084686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003338375	SCV004058314	pathogenic	Cardiovascular phenotype	2023-08-01	criteria provided, single submitter	clinical testing	The p.R636S pathogenic mutation (also known as c.1906C>A), located in coding exon 9 of the RBM20 gene, results from a C to A substitution at nucleotide position 1906. The arginine at codon 636 is replaced by serine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals with dilated cardiomyopathy (DCM) and has been shown to segregate with DCM across several families, some of which exhibited reduced penetrance (Brauch KM et al. J Am Coll Cardiol. 2009;54:930-41; Broendberg AK et al. Eur J Hum Genet. 2018 Mar;26(3):303-313; Hey TM et al. Circ Heart Fail. 2019 Mar;12(3):e005700; Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799). Functional studies have indicated that this variant adversely impacts protein function (Guo W et al. Nat Med. 2012;18:766-73; Wyles SP et al. Hum Mol Genet. 2016;25:254-65). Other alterations at the same codon, p.R636C (c.1906C>T) and p.R636H (c.1907G>A), have also been reported in association with DCM (Li D et al. Clin Transl Sci. 2010;3:90-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000000294	SCV000020438	pathogenic	Dilated cardiomyopathy 1DD	2009-09-01	no assertion criteria provided	literature only