Submissions for variant NM_001134363.3(RBM20):c.1913C>G (p.Pro638Arg)

dbSNP: rs267607003

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183864	SCV000236346	pathogenic	not provided	2017-05-08	criteria provided, single submitter	clinical testing	Although the P638R pathogenic variant in the RBM20 gene has not been published as pathogenic or been reported as benign to our knowledge, it has been identified in two unrelated individuals referred for DCM testing at GeneDx and segregates with DCM in several affected family members of one of these probands. Additionally, a pathogenic variant affecting this same residue (P638L) has been reported to segregate with DCM in multiple individuals from two unrelated families (Brauch et al., 2009). Furthermore, missense variants in nearby residues (R634W, R634Q, R636C, R636S, R636H) in the highly conserved Arginine/Serine-rich (RS) domain have been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. The P638R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs at a position that is conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, the P638R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517818	SCV003482864	likely pathogenic	Dilated cardiomyopathy 1DD	2022-09-23	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Pro6389 amino acid residue in RBM20. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19712804, 22466703). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 202063). 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 proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 638 of the RBM20 protein (p.Pro638Arg).
Ambry Genetics	RCV003165408	SCV003856988	uncertain significance	Cardiovascular phenotype	2023-03-03	criteria provided, single submitter	clinical testing	The p.P638R variant (also known as c.1913C>G), located in coding exon 9 of the RBM20 gene, results from a C to G substitution at nucleotide position 1913. The proline at codon 638 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a cohort of individuals with cardiovascular disease (VanDyke RE et al. J Genet Couns, 2021 Apr;30:503-512). Based on internal structural analysis, this alteration disrupts a characterized motif which has other known pathogenic variants (Watanabe T et al. Front Mol Biosci, 2018 Nov;5:105; Schneider JW et al. Nat Med, 2020 Nov;26:1788-1800; Nishiyama T et al. Sci Transl Med, 2022 Nov;14:eade1633). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.