ClinVar Miner

Submissions for variant NM_001134363.3(RBM20):c.1286T>C (p.Leu429Pro) (rs61735272)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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 RCV000036941 SCV000236333 likely benign not specified 2017-11-03 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000234102 SCV000286177 likely benign Dilated cardiomyopathy 1DD 2020-11-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622000 SCV000735574 likely benign Cardiovascular phenotype 2018-12-31 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
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 2020-02-03 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 Clinical Services Laboratory,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

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