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

dbSNP: rs397516862

Total submissions: 16

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, Mass General Brigham 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	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000037794	SCV000309780	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	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	RCV000172590	SCV000605336	likely benign	not provided	2020-02-03	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000584787	SCV000692519	benign	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	This alteration is classified as likely benign based on a combination of the following: 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.
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 Center for Human Genetics Tuebingen	RCV000172590	SCV000780572	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	TCAP: PM4:Supporting, BS2
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
Dept of Medical Biology, Uskudar University	RCV003318344	SCV004022030	benign	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1, BS2, PM4