Submissions for variant NM_003673.4(TCAP):c.97C>T (p.Arg33Trp)

gnomAD frequency: 0.00009  dbSNP: rs145524909

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000393182	SCV000333941	uncertain significance	not provided	2017-10-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546126	SCV000639707	uncertain significance	Hypertrophic cardiomyopathy 25; Primary familial hypertrophic cardiomyopathy	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 33 of the TCAP protein (p.Arg33Trp). This variant is present in population databases (rs145524909, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TCAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 282451). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256965	SCV001433505	uncertain significance	Hypertrophic cardiomyopathy 1	2019-08-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000393182	SCV001771622	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32233023, 16490376, 30564623, 28771489)
Ambry Genetics	RCV002374456	SCV002689580	uncertain significance	Cardiovascular phenotype	2024-03-27	criteria provided, single submitter	clinical testing	The p.R33W variant (also known as c.97C>T), located in coding exon 1 of the TCAP gene, results from a C to T substitution at nucleotide position 97. The arginine at codon 33 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a Wolff-Parkinson-White cohort and a hypertrophic cardiomyopathy cohort; however clinical details were limited and an additional alteration in another cardiac-related gene was identified in one case (Coban-Akdemir ZH et al. Am J Med Genet A, 2020 06;182:1387-1399; Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002480005	SCV002793593	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2G; Hypertrophic cardiomyopathy 25	2021-12-05	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV004764785	SCV005374775	uncertain significance	Hypertrophic cardiomyopathy 25		criteria provided, single submitter	clinical testing	The missense variant c.97C>T(p.Arg33Trp) in TCAP gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The observed variant has allele frequency of 0.006% in gnomAD exomes database. This variant has been submited to the ClinVar database as Uncertain Significance (VUS). Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change p.Arg33Trp in TCAP is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 33 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656143	SCV000678337	uncertain significance	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome