ClinVar Miner

Submissions for variant NM_001103.4(ACTN2):c.1484C>T (p.Thr495Met)

gnomAD frequency: 0.00027  dbSNP: rs200248944
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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 RCV000171827 SCV000054727 uncertain significance Hypertrophic cardiomyopathy 2018-04-05 criteria provided, single submitter research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000036880 SCV000060535 uncertain significance not specified 2016-06-16 criteria provided, single submitter clinical testing The p.Thr495Met variant in ACTN2 has been reported in at least 3 individuals wit h HCM, segregating with disease in 1 affected relative (Theis 2006, Chiu 2010). This variant has been previously identified by our laboratory in 3 individuals w ith HCM, one of which also carried a pathogenic variant in another gene. In addi tion, the p.Thr495Met variant in ACTN2 did not segregate with disease in two aff ected relatives from one family. This variant has also been identified in 22/651 34 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs200248944). Computational prediction tools and conser vation analysis suggest that this variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In summary, due t o conflicting data, the clinical significance of the p.Thr495Met variant is unce rtain.
Labcorp Genetics (formerly Invitae), Labcorp RCV000470355 SCV000553751 likely benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2024-01-22 criteria provided, single submitter clinical testing
GeneDx RCV001703876 SCV000617053 likely benign not provided 2021-04-07 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23299917, 24082139, 20022194, 23861362, 26656175, 26312134, 28518168, 17097056, 32880476)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769759 SCV000901181 uncertain significance Cardiomyopathy 2016-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000036880 SCV002500165 uncertain significance not specified 2022-03-07 criteria provided, single submitter clinical testing Variant summary: ACTN2 c.1484C>T (p.Thr495Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 251310 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 11 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 benign. c.1484C>T has been reported in the literature in an individual with Z-disk HCM within a cohort previously determined to be negative for mutations in the eight genes associated with myofilament-HCM (example, Theis_2006), in two individuals from a single family reportedly affected by HCM who were only screened for ACTN2 by high melt analysis (example, Chiu_2010), and as a VUS in settings of multigene panel testing in at-least two individuals among DCM cohorts (example, Akinrinade_2015, Verdonschot_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic/Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4; likely benign, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics RCV004018816 SCV003702198 uncertain significance Cardiovascular phenotype 2021-11-09 criteria provided, single submitter clinical testing The c.1484C>T (p.T495M) alteration is located in exon 13 (coding exon 13) of the ACTN2 gene. This alteration results from a C to T substitution at nucleotide position 1484, causing the threonine (T) at amino acid position 495 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
OMIM RCV000169901 SCV000222235 pathogenic Cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction 2010-03-16 no assertion criteria provided literature only

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