ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.76G>A (p.Asp26Asn) (rs727504399)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154575 SCV000204248 uncertain significance not specified 2013-02-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000766334 SCV000207707 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing p.Asp26Asn (GAT>AAT):c.76 G>A in exon 2 of the ACTC1 gene (NM_005159.4). The Asp26Asn variant in the ACTC1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp26Asn results in a semi-conservative amino acid substitution of a negatively charged Aspartic acid residue with a neutral, polar Asparagine residue at a position that is conserved across species. In silico analysis predicts Asp26Asn is probably damaging to the protein structure/function. Furthermore, the NHLBI ESP Exome Variant Server reports Asp26Asn was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in surrounding residues of the ACTC1 gene have been reported in association with HCM, suggesting this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Asp26Asn is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s).
Invitae RCV001054982 SCV001219346 pathogenic Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 26 of the ACTC1 protein (p.Asp26Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hypertrophic cardiomyopathy in families (PMID: 30600190), and has also been observed in individuals affected with ACTC1-related conditions (PMID: 30600190, 27532257). ClinVar contains an entry for this variant (Variation ID: 177917). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic.

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