ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.784-2A>G (rs794728964)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183252 SCV000235678 uncertain significance not specified 2012-09-28 criteria provided, single submitter clinical testing The c.784-2 A>G splice-site variant in the ACTN2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. This variant destroys the canonical splice acceptor site in intron 8 and is predicted to cause abnormal gene splicing. However, most mutations in the ACTN2 gene associated with DCM are missense changes. One frameshift mutation occurring at the end of the gene has been published in association with DCM. Therefore, the pathological effect of this splice-site variant occurring at the beginning of the ACTN2 gene cannot be interpreted for diagnosis or used for genetic counseling without further studies. With the clinical and molecular information available at this time, we cannot definitively determine if c.784-2 A>G is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Invitae RCV000472848 SCV000553763 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2016-11-06 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 of the ACTN2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ACTN2-related disease. ClinVar contains an entry for this variant (Variation ID: 201633). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ACTN2 cause disease. Therefore, this variant has been classified as a Variant of Uncertain Significance.

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