Submissions for variant NM_001134363.3(RBM20):c.3115C>T (p.Pro1039Ser)

gnomAD frequency: 0.00028  dbSNP: rs727503392

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151736	SCV000200093	likely benign	not specified	2018-08-22	criteria provided, single submitter	clinical testing	The p.Pro1039Ser variant in RBM20 is classified as likely benign because it has been identified in 0.04% (40/73076) of European chromosomes by the Genome Aggreg ation Database (gnomAD, http://gnomad.broadinstitute.org dbSNP rs727503392). Com putational prediction tools and conservation analysis suggest that the p.Pro1039 Ser variant may not impact the protein. ACMG/AMP Criteria applied: BS1_supportin g, BP4.
GeneDx	RCV000994517	SCV000236320	likely benign	not provided	2020-12-02	criteria provided, single submitter	clinical testing	Reported in association with sudden unexplained death and cardiomyopathy (Christiansen et al., 2016; van Lint et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29650543, 27650965, 30847666, 32840935)
Blueprint Genetics	RCV000208527	SCV000264174	uncertain significance	Primary dilated cardiomyopathy	2015-06-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000473528	SCV000360368	uncertain significance	Dilated cardiomyopathy 1DD	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000473528	SCV000552932	likely benign	Dilated cardiomyopathy 1DD	2024-01-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769276	SCV000900652	uncertain significance	Cardiomyopathy	2017-04-13	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852426	SCV000995110	uncertain significance	Hypertrophic cardiomyopathy	2017-06-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321626	SCV002607757	uncertain significance	Cardiovascular phenotype	2021-08-19	criteria provided, single submitter	clinical testing	The p.P1039S variant (also known as c.3115C>T), located in coding exon 11 of the RBM20 gene, results from a C to T substitution at nucleotide position 3115. The proline at codon 1039 is replaced by serine, an amino acid with similar properties. This variant has been reported in a family with dilated cardiomyopathy; however, some individuals also had a TTN variant detected (Hey TM et al. Circ Heart Fail, 2019 03;12:e005700). This variant has also been described in a sudden death case and in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional variants were detected in some cases (Christiansen SL et al. Eur J Hum Genet, 2016 12;24:1797-1802; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000473528	SCV002767461	likely benign	Dilated cardiomyopathy 1DD	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy, 1DD (MIM#613172). While some publications suggest a dominant negative mechanism for variants in the hotspot affecting residues between 630 and 640 (PMID: 32187365, PMID: 29895960), this mechanism has now been proven to be unlikely (PMID: 32840935). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Pathogenic variants in this gene have been described to be 66% penetrant, with age and sex also affecting penetrance (PMID: 30871348). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of cardiomyopathy, dilated, 1DD (MIM#613172). (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported multiple times, as both a VUS and likely benign. While this variant has been reported in at least five individuals with dilated cardiomyopathy, hypertrophic cardiomyopathy or sudden unexplained death, authors do not classify this variant as disease causing or pathogenic (LOVD, ClinVar, VCGS, PMID: 27650965, PMID: 30847666, PMID: 32840935, PMID: 29650543). In one family, affected individuals were also carriers of a pathogenic variant in the TTN gene (PMID: 30871348). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1004 - This variant has moderate functional evidence supporting normal protein function. Analysis of this variant in transfected cells by qRT-PCR, found it had no significant effect on the splicing of target genes and affected protein did not mislocalise. While the splicing of target gene TTN was not within control range, authors speculated this was not due to this variant and consequently classified this variant as likely benign (PMID: 32840935). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign