Submissions for variant NM_005159.5(ACTC1):c.622C>T (p.Arg208Cys)

gnomAD frequency: 0.00001  dbSNP: rs727505179

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156663	SCV000206384	uncertain significance	not specified	2014-08-11	criteria provided, single submitter	clinical testing	The p.Arg208Cys variant in ACTC1 has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction to ols and conservation analysis suggest that the variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In s ummary, the clinical significance of the p.Arg208Cys variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001319874	SCV001510636	uncertain significance	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2024-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 208 of the ACTC1 protein (p.Arg208Cys). This variant is present in population databases (rs727505179, gnomAD 0.06%). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 33500567). ClinVar contains an entry for this variant (Variation ID: 179863). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACTC1 protein function with a positive predictive value of 80%. 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.
GeneDx	RCV001529664	SCV002567408	uncertain significance	not provided	2022-08-04	criteria provided, single submitter	clinical testing	Identified in a patient with LVNC in published literature (Mazzarotto et al., 2021) and in patients with DCM referred for genetic testing at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33500567)
Ambry Genetics	RCV003162644	SCV003905417	uncertain significance	Cardiovascular phenotype	2023-01-18	criteria provided, single submitter	clinical testing	The p.R208C variant (also known as c.622C>T), located in coding exon 4 of the ACTC1 gene, results from a C to T substitution at nucleotide position 622. The arginine at codon 208 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a left ventricular non-compaction (LVNC) cohort; however, clinical details were limited (Mazzarotto F et al. Genet Med, 2021 May;23:856-864). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529664	SCV001743492	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001529664	SCV001932378	uncertain significance	not provided		no assertion criteria provided	clinical testing