Submissions for variant NM_001134363.3(RBM20):c.224C>T (p.Ser75Leu)

gnomAD frequency: 0.00004  dbSNP: rs191342808

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183842	SCV000236324	uncertain significance	not provided	2015-05-01	criteria provided, single submitter	clinical testing	p.Ser75Leu (TCG>TTG): c.224 C>T in exon 2 of the RBM20 gene (NM_001134363.1). The Ser75Leu variant in the RBM20 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ser75Leu results in a non-conservative amino acid substitution of a polar Serine residue with a non-polar Leucine residue at a position that is conserved across species. In silico analysis predicts Ser75Leu is probably damaging to the protein structure/function. Another missense mutation (Leu83Ile) has been reported in association with DCM, further supporting the functional importance of this region of the protein. The Ser75Leu variant 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. However, Ser75Leu was observed in 2/176 alleles (1.1%) of Japanese ancestry in the 1000 genomes database, indicating this may be a benign variant in this population.With the clinical and molecular information available at this time, we cannot definitively determine if Ser75Leu is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705259	SCV000834248	benign	Dilated cardiomyopathy 1DD	2023-12-30	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770270	SCV000901702	uncertain significance	Cardiomyopathy	2016-06-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000705259	SCV001259970	uncertain significance	Dilated cardiomyopathy 1DD	2018-01-13	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256892	SCV001433390	likely benign	not specified	2019-02-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426888	SCV002728827	uncertain significance	Cardiovascular phenotype	2023-04-03	criteria provided, single submitter	clinical testing	The p.S75L variant (also known as c.224C>T), located in coding exon 2 of the RBM20 gene, results from a C to T substitution at nucleotide position 224. The serine at codon 75 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a family with dilated cardiomyopathy (DCM) and conduction disorders and who was also noted to have a truncating alteration in LMNA (Kawakami H et al. Int Heart J, 2018 May;59:531-541). This variant was detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases. (van Lint FHM et al, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001256892	SCV003934743	uncertain significance	not specified	2023-05-16	criteria provided, single submitter	clinical testing	Variant summary: RBM20 c.224C>T (p.Ser75Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 148312 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.224C>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy and cardiac conduction disorders without evidence of cosegregation with disease (Kawakami_2018), and these individuals also had a truncating variant in LMNA. This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29628476). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4) or benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.