ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.496C>T (p.Pro166Ser) (rs267606628)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463693 SCV000550885 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2016-10-05 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 166 of the ACTC1 protein (p.Pro166Ser). 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) and has not been reported in the literature in individuals with an ACTC1-related disease. A different missense substitution at this codon (p.Pro166Ala) has been determined to be pathogenic (PMID: 10966831). This suggests that the proline residue is critical for ACTC1 protein function and that other missense substitutions at this position may also be pathogenic. 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. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000520468 SCV000618999 uncertain significance not provided 2019-01-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACTC1 gene. The P166S variant has not been published as pathogenic or been reported as benign to our knowledge. However, it is classified in ClinVar as a variant of uncertain significance by a different clinical laboratory (ClinVar SCV000550885.1; Landrum et al., 2016). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P166S 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. Additionally, 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. Furthermore, a missense variant at the same residue (P166A) has been reported to have occurred de novo in a male diagnosed with HCM at 17 months old (Olson et al., 2000), supporting the functional importance of this residue. Nevertheless, this variant has not been observed in a significant number of affected individuals and it lacks both segregation and functional studies which would further clarify its pathogenicity.

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