ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.26A>G (p.Gln9Arg) (rs121434525)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172514 SCV000050883 likely benign Primary dilated cardiomyopathy 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036908 SCV000060563 uncertain significance not specified 2016-06-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Gln9Arg varia nt in ACTN2 has been reported in 2 infants and 2 adults with DCM (including 1 ca rrying a pathogenic variant in another gene), 1 adult with DCM, Afib, AVNRT, 3 a dults with HCM, segregating with disease in 1 affected family member, (and inclu ding 1 carrying a pathogenic variant in another gene), 2 teenagers with LV dilat ion, and 1 adult with LVH (Mohapatra 2003, Bos 2006 abstract, LMM data).This var iant has been identified in 0.1% (71/64536) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121434525 ). In vitro functional studies provide some evidence that the p.Gln9Arg variant may impact protein function (Mohapatra 2003). However, these types of assays may not accurately represent biological function. While animal models provide some evidence for a disease-causing role, this has yet to be confirmed in patients (S anchez 2005 abstract). In summary, while the clinical significance of the p.Gln 9Arg variant is uncertain, these data suggest that it is more likely to be benig n.
GeneDx RCV000036908 SCV000235701 uncertain significance not specified 2017-07-04 criteria provided, single submitter clinical testing The Q9R variant in the ACTN2 gene has been reported in a 7 year-old male who died after acute onset of DCM (Mohapatra et al., 2003). His father also died with acute onset of DCM at 42 years of age. Although the proband's asymptomatic mother did not harbor the variant, a sample from the deceased father was not available to establish inheritance. Of note, molecular analysis in the Mohapatra et al. (2003) study included only two genes associated with DCM. The Q9R variant has been reported in one additional individual with DCM, who had extensive molecular analysis of 126 cardiac genes (Cuenca et al., 2016). However, the variant was inherited from this individual's father who had a normal cardiac evaluation, and it was present in multiple paternal relatives who also had normal cardiac evaluations. Furthermore, the affected sibling of this proband did not harbor the Q9R variant, showing lack of segregation of the variant with disease and suggesting the variant may not be disease-causing. The Q9R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. Moreover, this variant is located in the actin-binding domain which plays a crucial role in the initiation of myocyte cell differentiation. Immunoprecipitation studies showed that, in the presence of the Q9R variant, the ACTN2-encoded protein was not transported into the nucleus of myoblast cells, suggesting Q9R may prevent proper ACTN2 localization to the nucleus (Mohapatra et al., 2003). Nevertheless, this conclusion was solely based on the study of undifferentiated cells, whereas the ACTN2-encoded protein is localized and functions at the Z-disc of mature cardiomyocytes. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Lastly, the Q9R variant is observed in approximately 0.1-0.3% of alleles from individuals of European ancestry in large population cohorts, indicating it may be a rare benign variant in this population (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Ambry Genetics RCV000245795 SCV000318692 likely benign Cardiovascular phenotype 2019-11-01 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000461895 SCV000563590 likely benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2020-12-06 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000036908 SCV000740542 likely benign not specified 2017-05-23 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769743 SCV000901165 uncertain significance Cardiomyopathy 2017-03-29 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000019977 SCV001257481 uncertain significance Dilated cardiomyopathy 1AA 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
OMIM RCV000019977 SCV000040275 pathogenic Dilated cardiomyopathy 1AA 2003-09-01 no assertion criteria provided literature only

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