ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.554C>T (p.Ser185Leu) (rs730880054)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000382707 SCV000360574 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000290071 SCV000360575 uncertain significance Myofibrillar Myopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000472568 SCV000550835 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2018-04-28 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 185 of the BAG3 protein (p.Ser185Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs730880054, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 180282). 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: "Tolerated"; PolyPhen-2: "Possibly 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.
Blueprint Genetics RCV000157121 SCV000206844 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-07-23 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786110 SCV000924762 uncertain significance not provided 2016-10-13 no assertion criteria provided provider interpretation p.Ser185Leu (c.554C>T) in exon 3 of the BAG3 gene (NM_004281.3) We have seen this variant in a person with HCM. Testing was done by Invitae. Given the lack of case data and relatively high frequency in a population dataset, we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). It is listed in ClinVar by BluePrint Genetics, classified as a variant of uncertain significance. No phenotypica data is listed, but it was noted that the variant was found together with pathogenic MYH7 variant c.2609G>A. It has not been reported in the literature (as of 10/13/2016). The Invitae report notes, "The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0")." The variant was reported online in 16 of 280,452 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on 126,216 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 13 of 62,672 individuals of non-Finnish European descent (0.01% MAF) and 1 of 18,217 Latino people (0.0027%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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