Submissions for variant NM_001134363.3(RBM20):c.1900C>T (p.Arg634Trp)

dbSNP: rs796734066

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472655	SCV000552915	pathogenic	Dilated cardiomyopathy 1DD	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 634 of the RBM20 protein (p.Arg634Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (DCM) (PMID: 20590677, 29447731, 29540472, 29895960, 30557877). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 411653). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RBM20 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects RBM20 function (PMID: 29895960). This variant disrupts the p.Arg634 amino acid residue in RBM20. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19712804, 20590677, 22466703, 29029073). 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.
GeneDx	RCV000497722	SCV000589480	pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Reported in multiple unrelated individuals with DCM or left ventricular dysfunction (Li et al, 2010; Refaat et al., 2012; Hazebroek et al., 2018; van Waning et al., 2018; van den Hoogenhof et al., 2018; Pantou et al., 2018; Horvat et al., 2019; Das and Seth, 2021; Liatakis et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); 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: 30847666, 32880476, 33671899, 34021826, 34322310, 30557877, 22004663, 29892087, 20590677, 29540472, 29447731, 29650543, 32674065, 35653365)
Ambry Genetics	RCV002411511	SCV002723638	pathogenic	Cardiovascular phenotype	2024-03-05	criteria provided, single submitter	clinical testing	The p.R634W pathogenic mutation (also known as c.1900C>T), located in coding exon 9 of the RBM20 gene, results from a C to T substitution at nucleotide position 1900. The arginine at codon 634 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is located in the highly conserved RSRSP stretch that contains the majority of pathogenic RBM20 mutations (Watanabe T et al. Front Mol Biosci, 2018;5:105). This alteration has been detected in multiple individuals with dilated cardiomyopathy (DCM) and has been reported to segregate with disease in several families (Li D et al. Clin Transl Sci, 2010 Jun;3:90-7; Hazebroek MR et al. Circ Heart Fail, 2018 03;11:e004682; Pantou MP et al. Cardiology, 2018 Dec;141:150-155; van den Hoogenhof MMG et al. Circulation, 2018 09;138:1330-1342; Horvat C et al. Genet. Med., 2019 01;21:133-143; Yao JV et al, 2020 Aug;6:499-502). Functional studies suggest that R634W disrupts the phosphorylation of the RSRSP stretch, causes mislocalization, and leads to diminished splicing regulation activity (Murayama R et al. Sci Rep, 2018 06;8:8970). Another alteration at the same codon, p.R634Q (c.1901G>A), has been detected in individuals with DCM (Li D et al. Clin. Trans. Sci. 2010 Jun;3(3):90-7; Brauch KM et al. J. Am. Coll. Cardiol. 2009 Sep;54(10):930-42). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000497722	SCV004226837	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	PP1_strong, PM1, PM2_supporting, PM5, PS4_moderate
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000497722	SCV000732918	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000497722	SCV001922357	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000497722	SCV001932400	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000497722	SCV001953065	pathogenic	not provided		no assertion criteria provided	clinical testing