ClinVar Miner

Submissions for variant NM_001134363.3(RBM20):c.1906C>T (p.Arg636Cys)

gnomAD frequency: 0.00001  dbSNP: rs267607002
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000036953 SCV000060609 uncertain significance not specified 2017-12-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg636Cys variant in RBM20 has been identified in 2 individuals with DCM and segregated w ith disease in 1 affected relative (Li 2010, LMM data). This variant was absent from large population databases; however, this frequency information may be unre liable as metrics indicate poor data quality at this position. This variant has also been reported in ClinVar (Variation ID: 43980). This variant lies within ex on 9, which encodes a conserved protein domain where other pathogenic variants h ave been reported (Brauch 2009, Li 2010). In addition, different disease-causing variants involving this amino acid position (p.Arg636His; p.Arg636Ser) have bee n reported in affected individuals, suggesting that the p.Arg636Cys variant may not be tolerated. In summary, while there is some suspicion for a pathogenic rol e, the clinical significance of the p.Arg636Cys variant is uncertain. ACMG/AMP C riteria applied: PS4_Supporting, PM1, PM5.
GeneDx RCV000225732 SCV000236343 pathogenic not provided 2021-11-22 criteria provided, single submitter clinical testing Reported in ClinVar (ClinVar Variant ID# 43980; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect as this variant may result in a protein trafficking defect (Brodehl et al., 2019); This variant is associated with the following publications: (PMID: 30262925, 21483645, 19712804, 30547036, 32160020, 20590677, 29961767, 30871351, 31317183, 31737537)
Labcorp Genetics (formerly Invitae), Labcorp RCV000170520 SCV000286187 pathogenic Dilated cardiomyopathy 1DD 2023-05-23 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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, 22466703, 23861363). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RBM20 function (PMID: 30262925). 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. ClinVar contains an entry for this variant (Variation ID: 43980). This missense change has been observed in individuals with clinical features of RBM20-related conditions and/or dilated cardiomyopathy (PMID: 20590677, 21483645, 31317183, 31737537; Invitae). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 636 of the RBM20 protein (p.Arg636Cys).
Ambry Genetics RCV002408510 SCV002722021 pathogenic Cardiovascular phenotype 2023-10-25 criteria provided, single submitter clinical testing The p.R636C pathogenic mutation (also known as c.1906C>T), located in coding exon 9 of the RBM20 gene, results from a C to T substitution at nucleotide position 1906. The arginine at codon 636 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in probands with dilated cardiomyopathy (DCM), has segregated with disease in two affected individuals in one family, and occurs in a RS-rich hot spot region (Li D et al. Clin Transl Sci. 2010;3:90-7; Minoche AE et al. Genet. Med.. 2019 03;21(3):650-662). One in vitro study reported this alteration to result in abnormal protein localization (Brodehl A et al. Genet. Med. 2018 Sep). Based on internal structural analysis, this variant is predicted to be structurally disruptive (Jang S et al. Nucleic Acids Res. 2019 May;47(9):4663-4683; Ambry internal data). In addition, other alterations involving the same amino acid, p.R636H (c.1907G>A) and p.R636S (c.1906C>A), have been detected in families with DCM (Brauch KM et al. J Am Coll Cardiol. 2009;54:930-41). 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 RCV000170520 SCV000223085 pathogenic Dilated cardiomyopathy 1DD 2010-06-01 no assertion criteria provided literature only

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