ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1235C>T (p.Thr412Met) (rs139515659)

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Total submissions: 10
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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 RCV000171860 SCV000054724 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036866 SCV000060521 uncertain significance not specified 2014-02-11 criteria provided, single submitter clinical testing The Thr412Met variant in ACTN2 has now been identified by our laboratory in four individuals, two with DCM and two with HCM, one of whom carried a pathogenic va riant in another gene. In addition, this variant has been identified in 1/8600 E uropean American chromosomes and in 1/4406 African American chromosomes by the N HLBI Exome Sequencing Project (; dbSNP rs1395156 59) and in 1/1740 European chromosomes by the ClinSeq study (Ng 2013). Threonine (Thr) at position 412 is conserved in mammals, but not in evolutionarily distan t species and 2 fish species carry a methionine (Met) at this position, raising the possibility that this change may be tolerated. Computational prediction tool s also suggest this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Additional information is ne eded to fully assess the clinical significance of this variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000171860 SCV000225268 uncertain significance not provided 2014-12-16 criteria provided, single submitter clinical testing
GeneDx RCV000036866 SCV000235683 likely benign not specified 2017-12-05 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.
Ambry Genetics RCV000249512 SCV000318143 uncertain significance Cardiovascular phenotype 2020-02-28 criteria provided, single submitter clinical testing The p.T412M variant (also known as c.1235C>T), located in coding exon 11 of the ACTN2 gene, results from a C to T substitution at nucleotide position 1235. The threonine at codon 412 is replaced by methionine, an amino acid with similar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort , in two individuals with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes, and in one sudden death case with limited clinical information provided ((Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46; Pugh TJ et al. Genet Med. 2014;16(8):601-8; Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:[Epub ahead of print]). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000469241 SCV000553771 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 412 of the ACTN2 protein (p.Thr412Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs139515659, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with dilated cardiomyopathy (PMID: 24503780) and in an individual that suffered sudden death by unknown cause (PMID: 29247119). ClinVar contains an entry for this variant (Variation ID: 43897). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000515372 SCV000611337 uncertain significance Dilated cardiomyopathy 1AA 2017-05-23 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000036866 SCV000740536 uncertain significance not specified 2017-01-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000171860 SCV001147734 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170467 SCV001333047 likely benign Cardiomyopathy 2018-01-02 criteria provided, single submitter clinical testing

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