Submissions for variant NM_003673.4(TCAP):c.316C>T (p.Arg106Cys)

gnomAD frequency: 0.00813  dbSNP: rs45578741

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172591	SCV000051422	likely benign	Primary familial hypertrophic cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037793	SCV000061455	benign	not specified	2015-05-18	criteria provided, single submitter	clinical testing	p.Arg106Cys in exon 2 of TCAP: This variant is not expected to have clinical sig nificance because it has been identified in 17.4% (1953/11200) of Latino chromos omes, including 177 homozygotes, by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org/; dbSNP rs45578741). Of note, this variant was initia lly described as disease-causing based on its identification in 2 Caucasian indi viduals with HCM and absence from 400 healthy controls (Perrot 2006, Andersen 20 08).
Eurofins Ntd Llc (ga)	RCV000037793	SCV000112239	benign	not specified	2014-03-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000037793	SCV000153009	benign	not specified	2017-04-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000586561	SCV000171971	benign	not provided	2018-11-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24037902, 23299917, 19035361, 27535533, 30847666)
Invitae	RCV001082352	SCV000287956	benign	Hypertrophic cardiomyopathy 25; Primary familial hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000037793	SCV000309778	likely benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000245436	SCV000318085	benign	Cardiovascular phenotype	2019-05-13	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586561	SCV000605337	benign	not provided	2023-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586561	SCV000698214	likely benign	not provided	2017-06-12	criteria provided, single submitter	clinical testing	Variant summary: The TCAP c.316C>T (p.Arg106Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2260/116004 control chromosomes (178 homozygotes) at a frequency of 0.0194821, which is approximately 779 times the estimated maximal expected allele frequency of a pathogenic TCAP variant (0.000025), suggesting this variant is likely a benign polymorphism. The frequency of this variant is particularly higher in Latino populations (0.1744 in ExAC and 0.1526 in GnomAD). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. This variant was reported in HCM (n=1), DCM (n=2), and familial secundum-type atrial septal defect (n=1); however, causal role of the variant in none of the patients has been established. This variant was found in 2 cases where it was co-occurring with TNNI3 c.433C>T, p.Arg145Trp (pathogenic in our internal database) (Anderson_HM_2008) and 2 cases with sudden unexpected death in infancy, both in European (Danish) population. Taken together, this could be a functional polymorphism or modifier; therefore, this variant was classified as likely benign until further co-segregation and functional studies become available.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770526	SCV000901972	benign	Cardiomyopathy	2015-10-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001122674	SCV001281420	benign	Autosomal recessive limb-girdle muscular dystrophy type 2G	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001122675	SCV001281421	benign	Hypertrophic cardiomyopathy 25	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001258227	SCV001435129	benign	Hypertrophic cardiomyopathy		criteria provided, single submitter	research	The heterozygous p.Arg106Cys variant in TCAP has been identified in at least 1 Danish individual with hypertrophic cardiomyopathy (PMID: 19035361). This variant is classified as benign for autosomal dominant hypertrophic cardiomyopathy because it has been identified in >17% of Latino chromosomes and 178 total homozygotes by ExAC (http://gnomad.broadinstitute.org/).
Athena Diagnostics Inc	RCV000037793	SCV001477044	benign	not specified	2019-12-27	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000586561	SCV001742001	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000037793	SCV001922554	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000586561	SCV001932007	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000037793	SCV001953721	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586561	SCV001966327	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000586561	SCV002037090	likely benign	not provided		no assertion criteria provided	clinical testing