ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.998C>T (p.Ala333Val) (rs730880406)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157801 SCV000207731 likely pathogenic not provided 2012-09-04 criteria provided, single submitter clinical testing p.Ala333Val (GCT>GTT): c.998 C>T in exon 7 of the ACTC1 gene (NM_005159.4). The Ala333Val variant in the ACTC1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Ala333Val results in a conservative amino acid substitution of one non-polar amino acid with another, the Ala333 position is highly conserved across species. In silico analysis predicts Ala333Val is possibly damaging to the protein structure/function. Mutations in this codon (Ala333Pro) and in nearby codons (Ala323Val, Glu363Gly) have been reported in association with cardiomyopathy further supporting the functional importance of this codon and this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Ala333Val was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, while Ala333Val 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 DCM panel(s).
Invitae RCV001034914 SCV001198217 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 333 of the ACTC1 protein (p.Ala333Val). 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 individual(s) with clinical features of dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 180773). 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. This variant disrupts the p.Ala333 amino acid residue in ACTC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10966831, 24793351, 24736382). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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