ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.968C>T (p.Ala323Val) (rs730880404)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157799 SCV000207729 pathogenic not provided 2014-01-26 criteria provided, single submitter clinical testing p.Ala323Val (GCT>GTT): c.968 C>T in exon 6 of the ACTC1 gene (NM_005159.4). The A323V mutation in the ACTC1 gene has been reported in one patient with HCM (Maron B et al., 2012). Maron et al. identified A323V in an 18 year old male with HCM who harbored another mutation in the MYBPC3 gene and had a family history of sudden cardiac death. This study did not observed this mutation in 300 control chromosomes. Additionally, A323V 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 A323V mutation 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 A323 residue is highly conserved across species. Mutations in nearby residues (R314H, A333P) have been reported in association with cardiomyopathy further supporting the functional importance of this region of the protein. In summary, A323V in the ACTC1 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Center for Human Genetics,University of Leuven RCV000768495 SCV000886800 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000819426 SCV000960085 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 323 of the ACTC1 protein (p.Ala323Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 28790153, 21839045, Invitae). ClinVar contains an entry for this variant (Variation ID: 180771). 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.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000768495 SCV001156282 likely pathogenic Hypertrophic cardiomyopathy 2018-05-02 criteria provided, single submitter research The ACTC1 Ala323Val has been reported previously in a HCM proband carrying another variant in a sarcomere gene, the proband was reported to have a family history of sudden cardiac death (Maron MS, et al., 2012). The variant has also been identified by another laboratory in at least 4 HCM probands and 2 family members (Genedx, personal communication). ACTC1 Ala323Val is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a HCM proband with a family history of HCM. The variant was found to segregate with disease in an uncle and first cousin-once removed. A second variant (MYL3 Ala75Asp) was also identified in the cousin but did not segregate to the proband or uncle. Computational tools predict this variant to have a deleterious effect (SIFT: "Deleterious"; MutationTaster: Disease-causing"; CADD score: 25.4). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant has been reported in at least 2 HCM probands (PS4_supporting), in silico tools predict it to be deleterious (PP3), segregates with multiple affected family members (PP1_moderate) and is rare in the general population (PM2), therefore we classify ACTC1 Ala323Val as "likely pathogenic ".

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