ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.268C>T (p.His90Tyr) (rs121912676)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038323 SCV000061992 uncertain significance not specified 2015-09-09 criteria provided, single submitter clinical testing The p.His90Tyr variant in ACTC1 has been reported in 3 individuals with HCM (Mor ita 2008, LMM unpublished data). This variant has also been identified in 1/6673 0 European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs121912676). Computational prediction tools and conserv ation analysis suggest that the p.His90Tyr variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, the clinical significance of the p.His90Tyr variant is uncertain.
GeneDx RCV000038323 SCV000207709 uncertain significance not specified 2016-02-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACTC1 gene. The H90Y variant has been reported in one individual with idiopathic left ventricular hypertrophy diagnosed before the age of 15 years, and was absent from more than 1000 control chromosomes (Morita et al., 2008); however, in vitro functional studies and additional clinical information was not included. In addition, the H90Y variant has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (Landrum et al., 2014). Nevertheless, the H90Y 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. The H90Y 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 and occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000697168 SCV000825765 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2018-05-25 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 90 of the ACTC1 protein (p.His90Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs121912676, ExAC 0.001%). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 28356264). ClinVar contains an entry for this variant (Variation ID: 18326). 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.
OMIM RCV000019991 SCV000040289 pathogenic Familial hypertrophic cardiomyopathy 11 2008-05-01 no assertion criteria provided literature only

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