ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.886T>C (p.Tyr296His) (rs730880402)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157797 SCV000207727 likely pathogenic not provided 2013-11-20 criteria provided, single submitter clinical testing p.Tyr296His (TAT>CAT): c.886 T>C in exon 6 of the ACTC1 gene (NM_005159.4). The Tyr296His variant in the ACTC1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Tyr296His variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The Ty296 residue is conserved across species. In silico analysis predicts Tyr296His is possibly damaging to the protein structure/function. Mutations affecting nearby residues (Ala297Ser, Met307Leu) have been reported in association with HCM further supporting the functional importance of this region of the protein. Furthermore, the Tyr296His 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 summary, while Tyr296His is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in HCM panel(s).
Invitae RCV000822288 SCV000963083 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2018-08-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 296 of the ACTC1 protein (p.Tyr296His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 180769). 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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