ClinVar Miner

Submissions for variant NM_003673.4(TCAP):c.34GAG[1] (p.Glu13del) (rs397516862)

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Total submissions: 15
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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 RCV000172590 SCV000055309 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037794 SCV000061456 benign not specified 2019-05-10 criteria provided, single submitter clinical testing The p.Glu13del variant in TCAP is classified as benign because it has been identified in 0.4% (43/10340) of Ashkenazi Jewish chromosomes (including one homozygote) and in 0.1% (182/128862) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1.
GeneDx RCV000172590 SCV000236405 likely benign not provided 2014-10-28 criteria provided, single submitter clinical testing The variant is found in DCM,CARDIOMYOPATHY panel(s).
Invitae RCV001081397 SCV000287959 likely benign Hypertrophic cardiomyopathy 25; Primary familial hypertrophic cardiomyopathy 2020-12-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000037794 SCV000309780 likely benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000037794 SCV000334233 likely benign not specified 2015-08-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000037794 SCV000597410 uncertain significance not specified 2016-09-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001281804 SCV000605336 likely benign none provided 2020-02-03 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000584787 SCV000692519 benign Familial hypertrophic cardiomyopathy 1 2017-03-16 criteria provided, single submitter research The TCAP Glu13del variant has been previously identified in multiple HCM and DCM patients (Bos JM, et al., 2006; Perrot A, et al., 2006; Marziliano N, et al., 2006; Anderson PS, et al., 2009; Hirtle-Lewis M, et al., 2013; Pugh TJ, et al., 2014), however it has also been identified control cohorts at an allele frequency of up to 0.5% (Perrot A, et al., 2006; Marziliano N, et al., 2006; Anderson PS, et al., 2009). In vitro functional evaluations have shown that the TCAP Glu13del variant causes improper formation of telethonin β-hairpin structure necessary for titin binding, that may in fact be harmless (Knoll R, et al., 2011). The variant is present in the Exome Aggregation Consortium dataset (MAF= 0.00095; http://exac.broadinstitute.org/). We identified this variant in 3 HCM probands. In one of these families both the proband and an affected family member also carried a second pathogenic variant (MYBPC3 p.Pro955Argfs*95). In another family it was found to cosegregate in two affected family members, but did not segregate to a third affected family member. In summary, based on identification of the variant in controls, high allele frequency, as well as the lack of segregation in our family, we classify TCAP Glu13del as a "benign" variant.
Ambry Genetics RCV000617480 SCV000735729 likely benign Cardiovascular phenotype 2018-08-06 criteria provided, single submitter clinical testing No disease association in small case-control study;Other data supporting benign classification
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000037794 SCV000740383 likely benign not specified 2017-04-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172590 SCV000780572 likely benign not provided 2019-07-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037794 SCV000920302 benign not specified 2018-09-03 criteria provided, single submitter clinical testing Variant summary: TCAP c.37_39delGAG (p.Glu13del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 0.001 in 276952 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 40-fold of the estimated maximal expected allele frequency for a pathogenic variant in TCAP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. The variant, c.37_39delGAG, has been reported in the literature in individuals affected with Cardiomyopathy as well as in controls (Marziliano_2006, Perrot_2006). In vitro studies have shown the variant to result in the inability to bind the titin N-terminus due to the loss of proper formation of the telethonin B-hairpin structure, which the authors state may in fact be harmless (Knoll_2011). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. One cardiology center (via ClinVar), reports the variant in HCM family members who also carried a pathogenic MYBPC3 variant, and in another family, the variant did not segregate with disease in all affected family members. Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000989845 SCV001140436 likely benign Hypertrophic cardiomyopathy 25 2019-05-28 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170354 SCV001332928 benign Cardiomyopathy 2018-03-08 criteria provided, single submitter clinical testing

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