ClinVar Miner

Submissions for variant NM_004281.3(BAG3):c.785C>T (p.Ala262Val) (rs397516883)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000247776 SCV000320178 uncertain significance Cardiovascular phenotype 2015-09-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
Blueprint Genetics RCV000788989 SCV000928298 uncertain significance not provided 2019-03-22 criteria provided, single submitter clinical testing
Invitae RCV000525923 SCV000650673 uncertain significance Myofibrillar myopathy, BAG3-related; Dilated cardiomyopathy 1HH 2017-04-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 262 of the BAG3 protein (p.Ala262Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs397516883, ExAC 0.01%) but has not been reported in the literature in individuals with a BAG3-related disease. ClinVar contains an entry for this variant (Variation ID: 44789). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037899 SCV000061561 uncertain significance not specified 2013-01-14 criteria provided, single submitter clinical testing The Ala262Val variant in BAG3 has not been reported in the literature, but has b een identified by our laboratory in 1 Caucasian infant with DCM, who also carrie d a likely pathogenic TNNT2 variant. The Ala262Val variant has not been identifi ed in large European American and African American populations by NHLBI Exome Se quencing Project (http://evs.gs.washington.edu/EVS), though it may be common in other populations. Alanine (Ala) at position 262 is not conserved in mammals or evolutionarily distant species and horse carries a valine (Val; this variant), s uggesting that this change may be tolerated. Additional computational analyses ( biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) also suggest that the Ala262Val variant may not impact the protein, though this information i s not predictive enough to rule out pathogenicity. A different variant (Ala262Th r) at the same position has been reported in two brothers with familial DCM (Nor ton 2011), though the significance of this variant is also unclear. In summary, additional information is needed to fully assess the clinical significance of th e Ala262Val variant.

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