ClinVar Miner

Submissions for variant NM_001134363.3(RBM20):c.2737G>A (p.Glu913Lys) (rs397516607)

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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,Partners HealthCare Personalized Medicine RCV000036973 SCV000060629 pathogenic Primary dilated cardiomyopathy 2017-06-14 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000497300 SCV000236360 pathogenic not provided 2019-01-16 criteria provided, single submitter clinical testing The E913K pathogenic variant in the RBM20 gene was initially reported in an individual with DCM who harbored additional variants of uncertain significance in the DSC2 and TTN genes (Pugh et al., 2014). This variant has subsequently been reported in another proband with DCM who experienced heart failure at 35-years-old, and E913K was found to segregate with complete penetrance in eight affected relatives (Beqqali et al., 2016). In addition, E913K has been reported in multiple unrelated individuals who have been referred to GeneDx laboratory for DCM testing. Moreover, E913K results in a non-conservative amino acid substitution at a position that is conserved across species. Functional studies by Beqqali et al. (2016) and Khan et al. (2016) have demonstrated that E913K leads to lower RBM20 protein levels and larger titin protein isoforms, as well as abnormal production of titin circular RNAs. Finally, the E913K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000647156 SCV000768943 likely pathogenic Dilated cardiomyopathy 1DD 2018-05-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 913 of the RBM20 protein (p.Glu913Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with familial dilated cardiomyopathy (PMID: 24503780) and has been reported to segregate with disease in a single family (PMID: 27496873). ClinVar contains an entry for this variant (Variation ID: 43998). Experimental studies have shown that this missense change decreases stability of the RBM20 protein, which alters TTN splicing and lowers the contractile force generated by sarcomeres (PMID: 27496873). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769275 SCV000900651 likely pathogenic Cardiomyopathy 2017-10-23 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000497300 SCV000924914 likely pathogenic not provided 2017-06-09 no assertion criteria provided provider interpretation Our patient is a 13 year-old male listed for heart tranplant due to familial DCM. He had a Comprehensive Cardiomyopathy Panel with the GeneDx laboratory which included sequencing of 76 genes and additional deletion/duplication analysis of 61 of those genes (nuclear genes) associated with various forms of cardiomyopathy: ABCC9 , ACTC (ACTC1), ACTN2, ANKRD1, BAG3 , BRAF, CAV3, CRYAB , CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, [no sequence data could be obtained for MYH6], MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL , NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. Results show that one variant was detected: p.Glu913Lys (E913K; c.2737G>A) in exon 11 of the RBM20 gene. Based on the information reviewed below, including very strong segregation data in a family with DCM, we classify p.Glu913Lys as Likely Pathogenic. This variant has been reported in the literature by Beqqali et al. (2016) in a family with DCM. It segregated with disease in 9 affected family members, which would happen by chance in 1/256 or 0.4% of cases. No other disease-causing variants were found in 83 DCM genes including TTN. The index patient presented with heart failure at age 35. His brother was diagnosed at age 19 and died of heart failure at age 29, His mother died of heart failure at age 72. Upon family-member screening, other family members were diagnosed with DCM at ages 12-17, and one of them underwent heart transplant at age 19. This paper also contains in vitro data on the variant. The authors report that it leads to lower RBM20 protein levels by affecting protein stability. This then causes altered splicing of titin (TTN) in the cardiomyocytes, resulting in a shift from the more stiff N2B isoform to the more compliant titin isoform N2BA, an increased sarcomere resting length, and decreased length-dependent activation (impaired Frank-Starling mechanism). In a separate paper (Khan et al. 2016), this same group shows the variant to alter formation of circular RNAs from TTN. This variant in RBM20 has been identified by LMM laboratory in 2 adults with DCM, according to their submission to ClinVar, for a total of 4 DCM families known to have it, including our patient's. It is absent from the gnomAD population database of 140,000 individuals. However, there is poor sequencing coverage at this location with only 65% of samples covered at 1x, much less 20x. This is a nonconservative amino acid change, resulting in the replacement of a negatively charged Glutamic Acid with a positively charged Lysine. Glutamic Acid at this location is absolutely conserved across ~100 vertebrate species for which we have data. The adjacent residues are also highly conserved. While pathogenic variants in RBM20 have been reported in cases of DCM within exon 9 (Brauch 2009, Li 2010), the impact of variants in other regions of the gene is currently unclear. However, a nearby variant, p.Glu916Lys, is listed as Likely Pathogenic by LMM in ClinVar, as it was found to segregate with disease in 5 affected individuals, including 4 obligate carriers. Variants in the RBM20 gene have been reported in approximately 3% of patients with DCM (Refaat et al., 2012), but specifically in pediatric patients may represent a higher proportion: Pugh et al. (2014) found high-confidence RBM20 variants in over 6% of pediatric patients with DCM. Variants in RBM20 are relatively newly reported with cardiomyopathy, so only minimal data on disease-associated variation in this gene is available. Currently, only 16 Likely Pathogenic or Pathogenic variants in this gene are listed in ClinVar (as of June 2017).

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