ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.322G>T (p.Val108Leu) (rs730880053)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000648832 SCV000770653 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2017-12-15 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 108 of the BAG3 protein (p.Val108Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BAG3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786111 SCV000924763 uncertain significance not provided 2018-01-02 no assertion criteria provided provider interpretation Identified in 1 patient with HCM at our center. Testing performed at Invitae. SCICD Classification: variant of uncertain significance based on absence in the general population and lack of case data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Case data (not including our patient): 0 · ClinVar: not present · Cases in the literature: none reported Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain" Of note, most disease-causing variants in BAG3 are nonsense or frameshift variants. Nearby pathogenic variants at this codon or neighboring codons: None Population data: Absent The variant is not listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Per Varsome.org, the average coverage at that site in genomes is 33x whereas in exomes it is 95x.

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