ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.793C>G (p.Gln265Glu) (rs727504323)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000252698 SCV000318473 uncertain significance Cardiovascular phenotype 2013-03-05 criteria provided, single submitter clinical testing
Invitae RCV000576286 SCV000677038 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2018-05-26 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 265 of the ACTC1 protein (p.Gln265Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a individual affected with hypertrophic cardiomyopathy  (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 177786). 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 tolerated, 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154413 SCV000204081 likely pathogenic Hypertrophic cardiomyopathy 2018-11-21 criteria provided, single submitter clinical testing The p.Gln265Glu variant in ACTC1 has been identified in 4 individuals with hyper trophic cardiomyopathy (HCM) and segregated with disease in 7 affected relatives (including 1 obligate carrier) from 3 families (LMM data, GeneDx pers. comm., A mbry pers. comm.). This variant has also been reported by other clinical laborat ories in ClinVar (Variation ID 177786) and was absent from large population stud ies. Computational prediction tools and conservation analysis do not provide str ong support for or against an impact to the protein. In summary, although additi onal studies are required to fully establish its clinical significance, this var iant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Supporting.

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