ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.10G>C (p.Asp4His) (rs730880408)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157803 SCV000207733 likely pathogenic not provided 2011-11-02 criteria provided, single submitter clinical testing This missense change is denoted p.Asp4His (aka D4H) at the protein level, and c.10 G>C at the cDNA level. The Asp4His variant in the ACTC1 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. Asp4His results in a non-conservative amino acid substitution of a negatively charged Aspartic acid with a positively charged Histidine at a residue that is conserved across species. In silico analysis predicts Asp4His is probably damaging to the protein structure/function (Kumar et al. 2009; Schwarz et al. 2010). In addition, the Asp4His variant was not detected in up to 200 alleles from control individuals of Caucasian ancestry tested at GeneDx, indicating it is not a common benign variant in this population. Furthermore, a different amino acid substitution at the same codon has been observed previously in other individuals tested for cardiomopathy at GeneDx. However, no disease-causing mutations have been reported in this region of the ACTC1 gene to date. In summary, while the Asp4His variant is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of the Asp4His variant at this time. The variant is found in DCM panel(s).
Invitae RCV000821482 SCV000962239 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 4 of the ACTC1 protein (p.Asp4His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ACTC1-related disease. ClinVar contains an entry for this variant (Variation ID: 180775). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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