ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.806T>C (p.Ile269Thr) (rs397517071)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038340 SCV000062011 likely pathogenic Primary dilated cardiomyopathy; Left ventricular noncompaction 2018-04-27 criteria provided, single submitter clinical testing The p.Ile269Thr variant has been identified in 3 individuals with early-onset ca rdiomyopathy and segregated with disease in 5 affected family members from 2 fam ilies (GeneDx pers. comm., LMM data). Phenotypes of these individuals included D CM, LVNC, and HCM. Severity in affected family members was variable raising the possibility that other genetic or environmental factors were present in the earl y onset cases. The p.Ile269Thr variant was absent from large population studies but has been reported in ClinVar (Variation ID# 45190). Computational prediction tools and conservation analysis suggest that the p.Ile269Thr variant may impact the protein, though this information is not predictive enough to determine path ogenicity. In summary, although additional studies are required to fully establi sh its clinical significance, the p.Ile269Thr variant is likely pathogenic. ACMG /AMP Criteria applied: PM2; PP1_Moderate; PP3; PS4_Supporting.
GeneDx RCV000157793 SCV000207723 likely pathogenic not provided 2014-02-11 criteria provided, single submitter clinical testing The I269T variant in the ACTC1 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism to our knowledge, but this variant has been observed in other unrelated individuals tested for DCM I269T results in a non-conservative amino acid substitution of a non-polar Isoleucine with a neutral, polar Threonine. While the Ile269 residue is not uniformly conserved across species, variation is limited to other non-polar amino acids at this position. In silico analysis predicts I269T is damaging to the protein structure/function. Mutations in nearby residues (M271V, S273F) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Furthermore, I269T 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 summary, I269T is a good candidate for a disease-causing mutation.

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