Submissions for variant NM_001103.4(ACTN2):c.441G>A (p.Ser147=)

gnomAD frequency: 0.00107  dbSNP: rs150182164

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000123506	SCV000166844	benign	not specified	2014-03-26	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	RCV000243478	SCV000318411	likely benign	Cardiovascular phenotype	2016-05-26	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	RCV001084569	SCV000563578	benign	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2024-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586835	SCV000697653	benign	not provided	2016-04-15	criteria provided, single submitter	clinical testing	Variant summary: Variant Summary: The c.441G.A (p.Ser147=) in ACTN2 gene is a synonymous change that involves a non-conserved nucleotide with a prediction of being a "disease-causing" by mutation taster. 4/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at an overall allele frequency of 0.036% (44/121320 chrs tested), mainly in individuals of African descent (0.32%; 33/10388 chrs tested). The observed frequency exceeds the maximum expected allele frequency for a pathogenic ACTN2 variant (0.0025%), suggesting that it is a common polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via published reports. Variant was identified in one individual undergoing genetic screening for CMYO panel, who tested positive for a known pathogenic variant in TTR. Lastly, the variant has been reported as Benign by a reputable database/clinical laboratory. Taken together, the variant was classified as Benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769747	SCV000901169	likely benign	Cardiomyopathy	2016-07-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000123506	SCV001365608	benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	p.Ser147Ser in Exon 04 of ACTN2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence and has been identified in 0.4% (14/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs150182164).
Clinical Genetics, Academic Medical Center	RCV000123506	SCV001920335	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000123506	SCV001973004	benign	not specified		no assertion criteria provided	clinical testing