Submissions for variant NM_003673.4(TCAP):c.472C>A (p.Arg158Ser)

dbSNP: rs397516863

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037798	SCV000061460	uncertain significance	not specified	2012-09-21	criteria provided, single submitter	clinical testing	The Arg158Ser variant in TCAP has not been reported in the literature. It has be en identified by our laboratory in 2 individuals with DCM, one of whom carried a second, likely pathogenic variant. Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this v ariant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of this variant.
Invitae	RCV000469810	SCV000551387	pathogenic	Hypertrophic cardiomyopathy 25; Primary familial hypertrophic cardiomyopathy	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 158 of the TCAP protein (p.Arg158Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant dilated cardiomyopathy (PMID: 26084686, 27532257; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44711). 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. This variant disrupts the p.Arg158 amino acid residue in TCAP. Other variant(s) that disrupt this residue have been observed in individuals with TCAP-related conditions (PMID: 24037902; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852468	SCV000995162	likely pathogenic	Hypertrophic cardiomyopathy	2018-12-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001555538	SCV001776976	likely pathogenic	not provided	2023-01-31	criteria provided, single submitter	clinical testing	Reported in several individuals with DCM or referred for DCM genetic testing (Pugh et al., 2014; Akinrinade et al., 2015; Walsh et al., 2017; Cuesta-Llavona et al., 2022); at least one individual harbored an additional variant that was thought to contribute to the phenotype (Pugh et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24503780, 27532257, 26084686, Cuesta-Llavona_2022_Cardiogenetics, 16490376)
Athena Diagnostics Inc	RCV001555538	SCV001879893	uncertain significance	not provided	2021-03-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001555538	SCV003827096	uncertain significance	not provided	2020-02-24	criteria provided, single submitter	clinical testing