Submissions for variant NM_001103.4(ACTN2):c.26A>G (p.Gln9Arg)

gnomAD frequency: 0.00070  dbSNP: rs121434525

Total submissions: 13

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, Mass General Brigham 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	RCV003327363	SCV000235701	likely benign	not provided	2023-05-11	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Ambry Genetics	RCV000245795	SCV000318692	likely benign	Cardiovascular phenotype	2019-11-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461895	SCV000563590	likely benign	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2024-01-31	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	likely benign	Cardiomyopathy	2023-05-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036908	SCV002598681	likely benign	not specified	2022-09-24	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224104	SCV003920192	uncertain significance	Dilated cardiomyopathy 1AA; Myopathy, congenital, with structured cores and z-line abnormalities; Myopathy, distal, 6, adult-onset, autosomal dominant	2021-03-30	criteria provided, single submitter	clinical testing	ACTN2 NM_001103.3 exon 1 p.Gln9Arg (c.26A>G): This variant has been reported in the literature in two individuals with DCM, but did not segregate with disease in one affected family member (Mohapatra 2003 PMID:14567970, Cuenca 2016 PMID:26899768). This variant is also present in 0.1% (135/116270) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-236849999-A-G) and is present in ClinVar (Variation ID:18313). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. An in vitro functional study did suggest an impact to the protein through disruption of interaction with MLP protein (Mohapatra 2003 PMID:14567970). However, this study may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Molecular Genetics, Royal Melbourne Hospital	RCV003993748	SCV004812508	likely benign	Intrinsic cardiomyopathy	2023-07-07	criteria provided, single submitter	clinical testing
OMIM	RCV000019977	SCV000040275	pathogenic	Dilated cardiomyopathy 1AA	2003-09-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004549383	SCV004743314	likely benign	ACTN2-related disorder	2022-09-14	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).