Submissions for variant NM_001103.4(ACTN2):c.870G>A (p.Ala290=)

gnomAD frequency: 0.00506  dbSNP: rs116464082

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036921	SCV000060576	benign	not specified	2012-01-06	criteria provided, single submitter	clinical testing	Ala290Ala in exon 9 of ACTN2: This variant is classified as benign because it do es not change the amino acid and is frequent in the general population (rs116464 082, NHLBI Exome Sequencing Project; MAF >1%).
GeneDx	RCV000036921	SCV000166847	benign	not specified	2013-05-07	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203682	SCV000262078	benign	Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy	2025-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000252759	SCV000318284	benign	Cardiovascular phenotype	2015-08-26	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768726	SCV000900096	benign	Cardiomyopathy	2015-09-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001100764	SCV001257300	likely benign	Dilated cardiomyopathy 1AA	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036921	SCV001362347	benign	not specified	2019-04-29	criteria provided, single submitter	clinical testing	Variant summary: ACTN2 c.870G>A alters a non-conserved nucleotide resulting in a synonymous change. 4/5 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 0.0013 in 251296 control chromosomes, predominantly at a frequency of 0.017 within the African or African-American subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 680 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACTN2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.870G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV004710449	SCV005264440	likely benign	not provided		criteria provided, single submitter	not provided
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV004710449	SCV005875843	likely benign	not provided	2024-09-16	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000036921	SCV001918280	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000036921	SCV001973660	benign	not specified		no assertion criteria provided	clinical testing