ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.2161C>A (p.Arg721Ser) (rs149433837)

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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 RCV000172516 SCV000054730 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154596 SCV000204269 uncertain significance not specified 2015-10-01 criteria provided, single submitter clinical testing The p.Arg721Ser variant in ACTN2 has been identified by our laboratory in 1 adul t with DCM and 4 adults with HCM. This variant has also been identified in 39/66 732 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.; dbSNP rs149433837). Computational prediction tools and conse rvation analysis suggest that the p.Arg721Ser variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, the clinical significance of the p.Arg721Ser variant is uncertain.
GeneDx RCV000154596 SCV000235698 likely benign not specified 2018-03-01 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001085915 SCV000285867 likely benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2020-11-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000245171 SCV000320255 likely benign Cardiovascular phenotype 2018-06-20 criteria provided, single submitter clinical testing Other strong data supporting benign classification
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768742 SCV000900112 benign Cardiomyopathy 2019-02-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001097371 SCV001253648 likely benign 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154596 SCV001339221 likely benign not specified 2020-03-10 criteria provided, single submitter clinical testing Variant summary: ACTN2 c.2161C>A (p.Arg721Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 251484 control chromosomes (gnomAD). The observed variant frequency is approximately 20.8- fold the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.2161C>A has been reported in the literature in at least one individual affected with Cardiomyopathy (Pugh_2014). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They cited the variant as likely benign (n=2) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256796 SCV001433246 uncertain significance Familial hypertrophic cardiomyopathy 1 2020-01-31 criteria provided, single submitter clinical testing

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