ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.536+10C>T (rs141219516)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036913 SCV000060568 benign not specified 2012-04-10 criteria provided, single submitter clinical testing 536+10C>T in Intron 05 of ACTN2: This variant is not expected to have clinical s ignificance because it is not located within the splice consensus sequence and h as been identified in 1.6% (58/3738) of African American chromosomes from a broa d population by the NHLBI Exome Sequencing Project ( /EVS; dbSNP rs141219516).
GeneDx RCV000036913 SCV000166845 benign not specified 2014-02-12 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.
Invitae RCV000456466 SCV000563575 benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2020-12-08 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000608566 SCV000743805 benign Dilated cardiomyopathy 1AA 2016-10-19 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769749 SCV000901171 benign Cardiomyopathy 2016-06-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000036913 SCV001361343 benign not specified 2019-06-24 criteria provided, single submitter clinical testing Variant summary: ACTN2 c.536+10C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 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 0.001 in 251394 control chromosomes, predominantly at a frequency of 0.014 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 560 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. c.536+10C>T has been reported in the literature in individual(s) affected with Hypertrophic Cardiomyopathy (Chiu_2010). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (TTR c.424G>A, p.Val142Ile; LabCorp), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000608566 SCV000733994 likely benign Dilated cardiomyopathy 1AA no assertion criteria provided clinical testing

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