ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1384G>T (p.Ala462Ser) (rs376923220)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000638621 SCV000760158 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2018-02-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 462 of the ACTN2 protein (p.Ala462Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs376923220, ExAC 0.003%). This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257). ClinVar contains an entry for this variant (Variation ID: 43905). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036874 SCV000060529 uncertain significance not specified 2012-05-02 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Ala462Ser v ariant (ACTN2) has not been reported in the literature nor previously identified by our laboratory. Alanine (Ala) at position 462 is highly conserved across evo lutionarily distant speicies, and computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impac t the protein, though this information is not predictive enough to determine pat hogenicity. Additional information is needed to fully assess the clinical signif icance of the Ala462Ser variant.

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