ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.2194G>A (p.Ala732Thr) (rs777744290)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000251386 SCV000320099 uncertain significance Cardiovascular phenotype 2015-08-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
GeneDx RCV000766344 SCV000235700 uncertain significance not provided 2018-09-10 criteria provided, single submitter clinical testing The Ala732Thr variant in the ACTN2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala732Thr results in a non-conservative amino acid substitution of a nonpolar Alanine with a polar Threonine at a position that is conserved across species. In silico analysis predicts Ala732Thr is damaging to the protein structure/function. The Ala732Thr variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby residues have been reported in association with DCM. With the clinical and molecular information available at this time, we cannot definitively determine if Ala732Thr are disease-causing mutations or rare benign variants. The variant is found in DCM panel(s).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000183273 SCV000271495 uncertain significance not specified 2015-12-03 criteria provided, single submitter clinical testing The p.Ala732Thr variant in ACTN2 has been identified by our laboratory in 2 indi viduals: 1 with HCM and 1 DCM. However, both individuals carried an additional v ariant of likely clinical significance (Zimmerman 2010, LMM unpublished data). The p.Ala732Thr variant has also been identified in 5/66736 of European chromoso mes by the Exome Aggregation Consortium (ExAC, Computational prediction tools and conservation analysis suggest that the p.Ala7 32Thr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala732Thr variant is uncertain.

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