Submissions for variant NM_001103.4(ACTN2):c.1341C>T (p.Phe447=)

gnomAD frequency: 0.00215  dbSNP: rs34785693

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036871	SCV000060526	benign	not specified	2012-03-22	criteria provided, single submitter	clinical testing	Phe447Phe in exon 12 of ACTN2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and has been identifie d in 0.4% (28/7020) of European American chromosomes from a broad, though clinic ally unspecified population (NHLBI Exome Sequencing Project; http://evs.gs.washi ngton.edu/EVS; dbSNP rs34785693).
GeneDx	RCV000036871	SCV000166851	benign	not specified	2013-10-03	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.
Ambry Genetics	RCV000241552	SCV000318179	likely benign	Cardiovascular phenotype	2015-05-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Invitae	RCV000456350	SCV000563592	benign	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768740	SCV000900110	benign	Cardiomyopathy	2016-09-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036871	SCV000918389	benign	not specified	2018-12-26	criteria provided, single submitter	clinical testing	Variant summary: ACTN2 c.1341C>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 variant allele was found at a frequency of 0.0025 in 277002 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 100-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV001701647	SCV004033011	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ACTN2: BP4, BP7, BS1
PreventionGenetics, part of Exact Sciences	RCV004549444	SCV004789773	benign	ACTN2-related disorder	2019-11-08	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000612145	SCV000734000	likely benign	Dilated cardiomyopathy 1AA		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036871	SCV001921503	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701647	SCV001927620	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000036871	SCV001951645	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001701647	SCV001964949	likely benign	not provided		no assertion criteria provided	clinical testing