ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.616A>C (p.Ile206Leu) (rs199700646)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226073 SCV000288307 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2019-06-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 206 of the BAG3 protein (p.Ile206Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs199700646, ExAC 0.009%). This variant has not been reported in the literature in individuals with BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 239790). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000443578 SCV000520095 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the BAG3 gene. The I206L variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. In silico analysis suggests that this variant is probably damaging to the protein structure/function. However, the I206L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Ambry Genetics RCV000617486 SCV000735872 uncertain significance Cardiovascular phenotype 2017-05-11 criteria provided, single submitter clinical testing Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000226073 SCV000894523 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-10-31 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852427 SCV000995111 uncertain significance Cardiomyopathy; Premature ventricular contraction 2019-01-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001104558 SCV001261432 likely benign Myofibrillar myopathy, BAG3-related 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001107313 SCV001264454 uncertain significance Dilated cardiomyopathy 1HH 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000443578 SCV000924759 uncertain significance not provided 2016-09-13 no assertion criteria provided provider interpretation

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