ClinVar Miner

Submissions for variant NM_005159.4(ACTC1):c.1112T>C (p.Ile371Thr) (rs730880407)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000245634 SCV000318918 uncertain significance Cardiovascular phenotype 2013-10-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770507 SCV000901952 uncertain significance Cardiomyopathy 2015-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000157802 SCV000207732 likely pathogenic not provided 2014-07-25 criteria provided, single submitter clinical testing p.Ile371Thr (ATT>ACT): c.1112 T>C in exon 7 of the ACTC1 gene (NM_005159.4). Mutations in the ACTC1 gene have been reported in approximately 1% of patients with autosomal dominant familial dilated cardiomyopathy (DCM) as well as some patients with autosomal dominant hypertrophic cardiomyopathy (HCM) (Cirino et al., 2011; Hershberger et al., 2009). The I371T variant is likely pathogenic and has not been published as a mutation or as a benign polymorphism to our knowledge. The I371T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the I371T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is completely conserved across species. Moreover, in silico analysis predicts this variant is possibly damaging to the protein structure/function. A missense mutation in a nearby residue (E363G) have been reported supporting the functional importance of this region of the protein.Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in CARDIOMYOPATHY panel(s).

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