Submissions for variant NM_001134363.3(RBM20):c.1286T>C (p.Leu429Pro)

gnomAD frequency: 0.00126  dbSNP: rs61735272

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036941	SCV000060597	likely benign	not specified	2012-11-30	criteria provided, single submitter	clinical testing	Leu429Pro in exon 3 of RBM20: This variant is not expected to have clinical sign ificance because it has been identified in 0.4% (13/3182) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/rs61735272). Leu429Pro in exon 3 of RBM20 (rs617352 72; allele frequency = 0.4%, 13/3182) **
GeneDx	RCV000757719	SCV000236333	likely benign	not provided	2022-02-11	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Invitae	RCV000234102	SCV000286177	likely benign	Dilated cardiomyopathy 1DD	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622000	SCV000735574	likely benign	Cardiovascular phenotype	2018-12-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000036941	SCV000740668	likely benign	not specified	2017-05-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000234102	SCV000886045	uncertain significance	Dilated cardiomyopathy 1DD	2022-09-12	criteria provided, single submitter	clinical testing	The p.Leu429Pro variant (rs61735272) has not been reported in the medical literature. The p.Leu429Pro variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.17% in the non-Finnish European population (identified in 122 out of 73,780 chromosomes), and is classified as likely benign by multiple labs in ClinVar (Variant ID: 43969). The leucine at codon 429 is weakly conserved considering 11 species (Alamut software v2.10.0), but computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.Leu429Pro variant cannot be determined with certainty.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770278	SCV000901710	uncertain significance	Cardiomyopathy	2016-04-12	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000770278	SCV000995334	likely benign	Cardiomyopathy	2019-01-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000234102	SCV001260071	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036941	SCV001467846	benign	not specified	2020-12-21	criteria provided, single submitter	clinical testing	Variant summary: RBM20 c.1286T>C (p.Leu429Pro) results in a non-conservative amino acid change located in the Matrin/U1-C-like C2H2-type zinc finger domain (IPR003604) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 151016 control chromosomes, predominantly at a frequency of 0.0021 within the Non-Finnish European subpopulation in the gnomAD database (v3.1), including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 45-fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1286T>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (i.e. 5 calling it likely benign and 5 classifying it as VUS). Based on the evidence outlined above, the variant was classified as benign.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000234102	SCV000536734	uncertain significance	Dilated cardiomyopathy 1DD	2015-08-20	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000234102	SCV000732912	likely benign	Dilated cardiomyopathy 1DD		no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000757719	SCV000925212	uncertain significance	not provided	2016-04-14	no assertion criteria provided	provider interpretation
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000757719	SCV001799657	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036941	SCV001925035	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000757719	SCV001931999	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000757719	SCV001952001	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000757719	SCV001969190	likely benign	not provided		no assertion criteria provided	clinical testing