ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1040C>T (p.Thr347Met) (rs727504590)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171859 SCV000050878 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155763 SCV000205474 uncertain significance not specified 2013-07-18 criteria provided, single submitter clinical testing The Thr347Met variant in ACTN2 has not been reported in individuals with cardiom yopathy or in large population studies. Computational analyses (biochemical amin o acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that th e Thr347Met variant may impact the protein, though this information is not predi ctive enough to determine pathogenicity. Additional information is needed to ful ly assess the clinical significance of this variant.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415429 SCV000492709 uncertain significance Syncope; Hypertrophic cardiomyopathy 2015-10-29 criteria provided, single submitter clinical testing
Invitae RCV001079030 SCV000760183 likely benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2019-12-31 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852594 SCV000995296 likely benign Cardiomyopathy 2019-01-31 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198290 SCV001369171 uncertain significance Dilated cardiomyopathy 1AA 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000155763 SCV001448531 likely benign not specified 2020-11-16 criteria provided, single submitter clinical testing Variant summary: ACTN2 c.1040C>T (p.Thr347Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251460 control chromosomes, predominantly at a frequency of 0.00098 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 39-fold 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 East Asian origin. c.1040C>T has been reported in the literature in individuals affected with Cardiomyopathy (e.g. Nunn_2016, Cuenca_2016). These reports 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. Four other ClinVar submitters (evaluation after 2014) reported the variant with conflicting assessments (likely benign, n=2; uncertain significance, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000171859 SCV001715417 uncertain significance not provided 2019-07-08 criteria provided, single submitter clinical testing

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