ClinVar Genomic variation as it relates to human health

The p.Arg636His variant in RBM20 has been reported in 5 individuals with DCM, se gregated with disease in >20 affected relatives (including multiple obligate car riers), and was absent from over 2000 control chromosomes (Brauch 2009, Li 2010, Wells 2013, LMM unpublished data). In summary, this variant meets our criteria to be classified as pathogenic for DCM in an autosomal dominant manner based upo n segregation studies and absence from controls.

Variant summary: RBM20 c.1907G>A (p.Arg636His) results in a non-conservative amino acid change located in the arginine/serine-rich region (RS) domain of the encoded protein sequence (Filippello_2013). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 154548 control chromosomes., c.1907G>A, has been reported in the literature in multiple individuals affected with Dilated Cardiomyopathy and was shown to segregate with disease in a large DCM family (example Wells_2013, Brauch_2009, Akinrinade_2015 and Garcia-Molina_2019 etc.). These data indicate that the variant is very likely to be associated with disease. Additionally, other variants affecting the same codon have also been reported in association with DCM (p.Arg636Cys, p.Arg636Ser), strongly suggesting the importance of the codon. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=6) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

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: 24503780, 27532257, 30871348, 26084686, 23861363, 20590677, 19712804, 25448463, 30471092, 30871351, 30972196, 31514951, 33906374, 34088380, 32851336, 33019804)

PS4, PP3, PM1, PM5

The RBM20 c.1907G>A variant is classified as Pathogenic (PS4, PP1_Strong, PM1, PM2, PP3) The RBM20 c.1907G>A variant is a single nucleotide change in exon 9/14 of the RBM20 gene, which is predicted to change the amino acid arginine at position 636 in the protein, to histidine. The variant has been reported in >15 probands with a clinical presentation of Dilated Cardiomyopathy (PMID#19712804, 20590677, 31514951, 30871348, ClinVar) (PS4) and is reported to co-segregate with disease in 7 meioses (PMID#23861363) (PP1_strong). This variant is located in the RBM20 enrichment region for variants associated with cardiomyopathy (exon 9) and different changes to this same amino acid are also reported as disease causing (PM1). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom) (PM2) is reported in dbSNP (rs267607004), is reported as disease causing in the HGMD database (CM095006) and is reported as pathogenic/likely pathogenic by other diagnostic laboratories (ClinVar #271) Computational predictions support a deleterious effect on the gene or gene product (PP3).

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 636 of the RBM20 protein (p.Arg636His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (DCM) (PMID: 19712804, 20590677, 23861363, 24503780, 26084686). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 271). 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. 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: 20590677, 21483645). 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.

The p.R636H pathogenic mutation (also known as c.1907G>A), located in coding exon 9 of the RBM20 gene, results from a G to A substitution at nucleotide position 1907. The arginine at codon 636 is replaced by histidine, an amino acid with highly similar properties. This mutation has been reported in several individuals with dilated cardiomyopathy (DCM), and has been shown to segregate with disease in multi-generational families with DCM (Brauch KM et al. J Am Coll Cardiol. 2009;54:930-41; Li D et al. Clin Transl Sci. 2010;3:90-7; Wells QS et al. Circ Cardiovasc Genet. 2013;6:317-26). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, other alterations at this codon (p.R636S and p.R636C) have also been reported in association with DCM (Brauch KM et al. J Am Coll Cardiol. 2009;54:930-41;Li D et al. Clin Transl Sci. 2010;3:90-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

The RBM20 c.1907G>A variant is predicted to result in the amino acid substitution p.Arg636His. This variant has been reported to be causative for dilated cardiomyopathy and found to segregate in multiple families (Brauch et al. 2009. PubMed ID: 19712804; Li et al. 2010. PubMed ID: 20590677; Table S1, Gigli et al. 2019. PubMed ID: 31514951). Functional studies showed that this variant results in aberrant subcellular localization (rat ortholog p.Arg639His in Figure 8, Zhang et al. 2023. PubMed ID: 37219949). This variant has not been reported in a large population database, indicating this variant is rare. Different nucleotide substitutions affecting the same amino acid (p.Arg636Ser, p.Arg636Cys, p.Arg636Leu) have been reported in individuals with dilated cardiomyopathy (Human Gene Mutation Database). Taken together, the c.1907G>A (p.Arg636His) variant is interpreted as pathogenic.