ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.769T>C (p.Phe257Leu) (rs730880399)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157791 SCV000207721 uncertain significance not provided 2014-07-23 criteria provided, single submitter clinical testing p.Phe257Leu (TTC>CTC): c.769 T>C in exon 5 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 as well as some patients with autosomal dominant hypertrophic cardiomyopathy (Cirino A et al., 2011; Hershberger Ret al., 2009).A variant of unknown significance has been identified in the ACTC1gene. The F257L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The F257L 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. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, only one missense mutation in a nearby residue (I252M) has been reported in association with dilated cardiomyopathy. Additionally, the F257L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM panel(s).
Ambry Genetics RCV000244970 SCV000320421 uncertain significance Cardiovascular phenotype 2015-11-11 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or conflicting evidence

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