Submissions for variant NM_005159.5(ACTC1):c.56_57insCA (p.Lys20fs)

gnomAD frequency: 0.00004  dbSNP: rs730880387

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460199	SCV000550879	uncertain significance	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys20Argfs*38) 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 present in population databases (rs730880387, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with atrial fibrillation (PMID: 34495297). ClinVar contains an entry for this variant (Variation ID: 180752). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223797	SCV002502357	uncertain significance	not provided	2022-01-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345531	SCV002648277	uncertain significance	Cardiovascular phenotype	2023-09-15	criteria provided, single submitter	clinical testing	The c.56_57insCA variant, located in coding exon 1 of the ACTC1 gene, results from an insertion of two nucleotides at position 56, causing a translational frameshift with a predicted alternate stop codon (p.K20Rfs*38). 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.
Fulgent Genetics, Fulgent Genetics	RCV000460199	SCV002800823	uncertain significance	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2021-10-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003531992	SCV004360327	uncertain significance	Cardiomyopathy	2023-05-10	criteria provided, single submitter	clinical testing	This variant inserts 2 nucleotides in exon 2 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. Clinical relevance of loss-of-function ACTC1 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. This variant has been identified in 2/31378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678694	SCV000804856	uncertain significance	not specified	2015-07-29	no assertion criteria provided	clinical testing