ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.310C>T (p.Pro104Ser) (rs397517059)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038325 SCV000061996 uncertain significance not specified 2015-12-22 criteria provided, single submitter clinical testing The p.Pro104Ser variant in ACTC1 has been reported in 2 Caucasian individuals wi th HCM and was absent from large population studies. Computational prediction to ols and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro104Ser variant is uncertain.
GeneDx RCV000484679 SCV000564544 likely pathogenic not provided 2015-01-05 criteria provided, single submitter clinical testing A novel P104S variant that is likely pathogenic was identified in the ACTC1 gene. It has not been published as a pathogenic variant or as a benign polymorphism to our knowledge. The P104S variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. In addition, the P104S 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. Moreover, this substitution occurs at a position that is completely conserved across species. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (R97C, E101K) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Invitae RCV001234157 SCV001406788 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2019-09-10 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 104 of the ACTC1 protein (p.Pro104Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ACTC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 45175). 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 disruptive, 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.

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