ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.523dup (p.His175fs)

dbSNP: rs730880389
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157774 SCV000207704 uncertain significance not provided 2013-08-06 criteria provided, single submitter clinical testing The c.523dupC variant in the ACTC1 gene has not been reported as a disease-causing mutation or as a benign change to our knowledge. This variant causes a shift in reading frame starting at codon Histidine 175, changing it to a Proline, and creating a premature stop codon at position 15of the new reading frame, denoted p.His175ProfsX15. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Nevertheless, no frameshift or nonsense mutations have been reported in the ACTC1 gene in association with cardiomyopathy.With the clinical and molecular information available at this time, we cannot definitively determine if c.523dupC is a disease-causing mutation or a rare benign variant.
Color Diagnostics, LLC DBA Color Health RCV001177862 SCV001342144 uncertain significance Cardiomyopathy 2023-10-25 criteria provided, single submitter clinical testing This variant inserts 1 nucleotide in exon 4 of the ACTC1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with ACTC1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Clinical significance of loss-of-function ACTC1 truncation variants in cardiomyopathy is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002336348 SCV002642426 uncertain significance Cardiovascular phenotype 2023-07-19 criteria provided, single submitter clinical testing The c.523dupC variant, located in coding exon 3 of the ACTC1 gene, results from a duplication of C at nucleotide position 523, causing a translational frameshift with a predicted alternate stop codon (p.H175Pfs*15). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of ACTC1 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV002516370 SCV003518641 uncertain significance Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2022-06-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His175Profs*15) in the ACTC1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ACTC1 cause disease. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACTC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 180754). 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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