Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Agnes Ginges Centre for Molecular Cardiology, |
RCV001089619 | SCV001245095 | likely pathogenic | Primary dilated cardiomyopathy | 2018-05-01 | criteria provided, single submitter | research | RBM20 Ser635Tyr has not been previously reported in any other cases and is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a DCM proband that was diagnosed after suffering a cardiac arrest, this proband has a family history of DCM and sudden death (segregation not possible). In silico tools, SIFT, MutationTaster and PolyPhen-2 predict the change to be deleterious. It is located in exon 9, a known hot-spot in DCM and another amino acid change at this position (Ser625Cys) has been classified as likely pathogenic. Based on the ACMG guidelines (Richards S, et al., 2015) this variant is located in a mutational 'hot-spot' (PM1), is rare in the general population (PM2), affects the same amino acid as another disease-causing variant (PM5) and in silico tools predict the variant to be disease-causing (PP3), therefore we classify RBM20 Ser635Tyr as 'likely pathogenic'. |
Invitae | RCV002555933 | SCV003218487 | uncertain significance | Dilated cardiomyopathy 1DD | 2022-07-03 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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) performed at Invitae indicates that this missense variant is expected to disrupt RBM20 protein function. ClinVar contains an entry for this variant (Variation ID: 870084). This variant has not been reported in the literature in individuals affected with RBM20-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 635 of the RBM20 protein (p.Ser635Tyr). |