ClinVar Miner

Submissions for variant NM_001134363.3(RBM20):c.1913C>T (p.Pro638Leu) (rs267607003)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211851 SCV000060611 pathogenic Primary dilated cardiomyopathy 2014-12-16 criteria provided, single submitter clinical testing The p.Pro638Leu variant in RBM20 has been reported in 3 families with DCM, segre gated with disease in >10 affected individuals (including 2 affected obligate ca rriers) and was absent from 2160 control chromosomes (Brauch 2009, Refaat 2012) and other large population studies. Additionally, this variant has been identifi ed by our laboratory in 2 individuals with DCM and LV dilation/dysfunction, 1 in dividual with atypical ARVC, and segregated with disease in 2 affected relatives . In vitro studies suggest that the p.Pro638Leu variant may impact protein funct ion (Guo 2012). Proline (Pro) at position 638 is highly conserved in mammals and evolutionarily distant species and lies within a conserved protein domain in wh ich other pathogenic variants have been reported (Brauch 2009, Li 2010). In summ ary, this variant meets our criteria to be classified as pathogenic for DCM in a n autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studies, absence from controls, and functional evidence.
GeneDx RCV000183865 SCV000236347 pathogenic not provided 2016-11-17 criteria provided, single submitter clinical testing The Pro638Leu mutation in the RBM20 gene has been reported previously in association with DCM (Brauch K et al., 2009). Brauch et al. identified the Pro638Leu through linkage analysis of a large family with three generations of individuals with DCM. The same study subsequently identified this mutation in a second family with multiple affected individuals and this mutation was absent from 960 control alleles. In addition, Pro638Leu was not observed in approximately 2,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Pro638Leu is located in exon 9 of RBM20, described as a mutation hot spot, and where mutations in nearby residues (Arg636Cys, Arg636His, Arg636Ser, Ser637Gly) have been reported in association with DCM (Brauch K et al., 2009). In summary, Pro638Leu in the RBM20 gene is interpreted as a disease-causing mutation.
Invitae RCV000000292 SCV000552923 pathogenic Dilated cardiomyopathy 1DD 2018-05-29 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 638 of the RBM20 protein (p.Pro638Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature to segregate with disease in two families with multiple members affected with dilated cardiomyopathy (DCM) (PMID: 19712804), as well as in one unrelated individual with DCM (PMID: 22004663). ClinVar contains an entry for this variant (Variation ID: 268). One experimental study has shown that this missense change disturbs RBM20 protein activity (PMID: 22466703). This variant lies within the RS domain of RBM20 that has been shown to be critical for the nuclear localization of the protein (PMID: 23886709). The majority of previously described disease causing variants in RBM20 are located in a stretch of 5 amino acids (p.Arg634-p.Pro638) within this domain (PMID: 19712804). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000619200 SCV000737224 pathogenic Cardiovascular phenotype 2017-01-19 criteria provided, single submitter clinical testing Strong segregation with disease (lod >3 = >10 meioses)
Fulgent Genetics,Fulgent Genetics RCV000000292 SCV000893836 pathogenic Dilated cardiomyopathy 1DD 2018-10-31 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256960 SCV001433497 pathogenic Dilated cardiomyopathy 1A 2020-05-04 criteria provided, single submitter clinical testing
OMIM RCV000000292 SCV000020436 pathogenic Dilated cardiomyopathy 1DD 2009-09-01 no assertion criteria provided literature only
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia RCV000490927 SCV000298124 pathogenic Dilated cardiomyopathy 1S 2016-05-01 no assertion criteria provided clinical testing

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