ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.541G>C (p.Asp181His)

dbSNP: rs730880393
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157783 SCV000207713 uncertain significance not provided 2012-10-11 criteria provided, single submitter clinical testing p.Asp181His (GAT>CAT):c.541 G>C in exon 4 of the ACTC1 gene (NM_005159.4). The Asp181His variant in the ACTC1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asp181His results in a non-conservative amino acid substitution of a negatively charged Aspartic acid residue with a positively charged Histidine residue at a position that is conserved across species. In silico analysis predicts Asp181His is possibly damaging to the protein structure/function. The NHLBI ESP Exome Variant Server reports Asp181His 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. However, no mutations have been reported in surrounding residues of the ACTC1 gene, indicating this region of the protein could be tolerant of change.With the clinical and molecular information available at this time, we cannot definitively determine if Asp181His is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Invitae RCV002515060 SCV003273124 uncertain significance Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2021-12-26 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 180758). This variant has not been reported in the literature in individuals affected with ACTC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 181 of the ACTC1 protein (p.Asp181His).

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