Submissions for variant NM_005159.5(ACTC1):c.1112T>C (p.Ile371Thr)

dbSNP: rs730880407

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157802	SCV000207732	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing	Has been reported in an individual with DCM (Haas et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25163546)
Ambry Genetics	RCV000245634	SCV000318918	uncertain significance	Cardiovascular phenotype	2019-02-08	criteria provided, single submitter	clinical testing	The p.I371T variant (also known as c.1112T>C), located in coding exon 6 of the ACTC1 gene, results from a T to C substitution at nucleotide position 1112. The isoleucine at codon 371 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy cohort, but clinical details were limited (Haas J et al. Eur. Heart J., 2015 May;36:1123-35a). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770507	SCV000901952	uncertain significance	Cardiomyopathy	2020-12-09	criteria provided, single submitter	clinical testing
Invitae	RCV001850192	SCV002135096	uncertain significance	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2023-02-01	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: 180774). This missense change has been observed in individual(s) with ACTC1-related conditions (PMID: 25163546; Invitae). This variant is present in population databases (rs730880407, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 371 of the ACTC1 protein (p.Ile371Thr).