Submissions for variant NM_006073.4(TRDN):c.1187-2A>G

dbSNP: rs578024729

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000680131	SCV000807574	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 5		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531412	SCV001538541	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002334239	SCV002634913	uncertain significance	Cardiovascular phenotype	2021-03-24	criteria provided, single submitter	clinical testing	The c.1187-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 17 in the TRDN gene. This variant was detected in a cardiomyopathy/arrhythmia genetic testing cohort and whole exome sequencing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases. (Yang Y et al. JAMA, 2014 Nov;312:1870-9; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV004588103	SCV005080028	uncertain significance	not provided	2023-07-10	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Observed in a patient with arrhythmia (PMID: 30847666); This variant is associated with the following publications: (PMID: 35932045, 30847666)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000680131	SCV005087199	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 5	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cardiac arrhythmia syndrome, with or without skeletal muscle weakness (MIM#615441). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0219 - This variant is non-coding in an alternative transcript. It is not present in NM_001256021.2, which encodes the predominant cardiac isoform, Trisk 32. (Hancox, J.C. et al. (2017)). In literature published up to August 2020, variants associated with arrhythmogenic syndromes are located in the first 208 amino acids of the protein (PMID: 33692971). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 88 heterozygotes, 2 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice site variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported as a VUS by a clinical testing laboratory and in several publications (ClinVar, PMIDs: 30847666, 35932045). It has also been reported as a predicted loss of function variant in a Pakistani myocardial infarction risk study, however no specific phenotypic information was provided for the variant carrier(s) (PMID: 28406212). Additionally, it has been reported as pathogenic by a clinical testing laboratory in two homozygous individuals in their childhood and without known arrhythmias (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003411589	SCV004115395	uncertain significance	TRDN-related disorder	2023-11-06	no assertion criteria provided	clinical testing	The TRDN c.1187-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in an individual via arrhythmia panel testing, however detailed phenotypic information was not provided (Supplementary File 2, van Lint et al 2019. PubMed ID: 30847666). This variant is reported in 0.44% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-123699045-T-C). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.