ClinVar Miner

Submissions for variant NM_001130004.2(ACTN1):c.1684G>A (p.Asp562Asn)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV003448715 SCV004176362 uncertain significance Platelet-type bleeding disorder 15 2023-02-14 criteria provided, single submitter clinical testing The missense c.1684G>A (p.Asp562Asn) variant in ACTN1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asp562Asn variant is reported with an allele frequency of 0.001% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has not been reported to the ClinVar database. The amino acid change p.Asp562Asn in ACTN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 562 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).
Labcorp Genetics (formerly Invitae), Labcorp RCV003778500 SCV004686111 uncertain significance not provided 2023-12-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 562 of the ACTN1 protein (p.Asp562Asn). This variant is present in population databases (rs147824601, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ACTN1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTN1 protein function with a negative predictive value of 80%. 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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