Submissions for variant NM_005159.5(ACTC1):c.1092C>T (p.Tyr364=)

gnomAD frequency: 0.00012  dbSNP: rs140261885

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038320	SCV000061989	likely benign	not specified	2015-07-02	criteria provided, single submitter	clinical testing	p.Tyr364Tyr in exon 7 of ACTC1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 3/10406 of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs140261885).
GeneDx	RCV000038320	SCV000520896	likely benign	not specified	2016-08-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038320	SCV000916414	benign	not specified	2018-07-09	criteria provided, single submitter	clinical testing	Variant summary: ACTC1 c.1092C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within African control individuals in the gnomAD database is approximately 17-fold of the estimated maximal expected allele frequency for a pathogenic variant in ACTC1 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.1092C>T, has been reported in the literature in individuals affected with Cardiomyopathy but also in controls and were classified as 'polymorphisms' (Tesson_2000, Takai_1999). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000866658	SCV001007784	likely benign	Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5	2024-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001183727	SCV001349537	likely benign	Cardiomyopathy	2019-02-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453315	SCV002736450	likely benign	Cardiovascular phenotype	2018-12-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003914946	SCV004728313	likely benign	ACTC1-related condition	2019-05-02	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).