ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1426G>A (p.Ala476Thr) (rs142943120)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620192 SCV000735696 likely benign Cardiovascular phenotype 2016-12-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172515 SCV000051362 likely benign not provided 2013-06-24 criteria provided, single submitter research
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769757 SCV000901179 uncertain significance Cardiomyopathy 2016-07-16 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000611565 SCV000734003 likely benign Dilated cardiomyopathy 1AA no assertion criteria provided clinical testing
GeneDx RCV000183261 SCV000235687 likely benign not specified 2017-11-15 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.
Illumina Clinical Services Laboratory,Illumina RCV000318194 SCV000355927 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000372792 SCV000355928 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000183261 SCV000916417 likely benign not specified 2018-11-19 criteria provided, single submitter clinical testing Variant summary: ACTN2 c.1426G>A (p.Ala476Thr) results in a non-conservative amino acid change located in one of the Spectrin repeats (IPR002017) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 277184 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0053 in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 210 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.1426G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS (2x), likely benign (3x), benign (1x)). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000234309 SCV000285859 benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2017-10-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000183261 SCV000269981 likely benign not specified 2017-07-27 criteria provided, single submitter clinical testing p.Ala476Thr in exon 13 of ACTN2: This variant is not expected to have clinical s ignificance because it has been identified in 0.53% (128/24020) of African chrom osomes by the Genome Aggregation Consortium (gnomAD, http://gnomad.broadinstitut e.org; dbSNP rs142943120).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000623286 SCV000740533 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-07-28 criteria provided, single submitter clinical testing

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