ClinVar Miner

Submissions for variant NM_006073.4(TRDN):c.1420+1G>T

gnomAD frequency: 0.00003  dbSNP: rs1375657667
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519329 SCV000621148 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TRDN gene. The c.1420+1 G>T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.1420+1 G>T variant is predicted to destroy the canonical splice donor site in intron 22 and may lead to abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, only one other splice site variant in the TRDN gene have been reported in HGMD in association with arrhythmia (Stenson et al., 2014).
Revvity Omics, Revvity RCV001783022 SCV002020284 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia 5 2021-08-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV002395255 SCV002699767 uncertain significance Cardiovascular phenotype 2023-07-11 criteria provided, single submitter clinical testing The c.1420+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 22 of the TRDN gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, this alteration does not impact the predominant cardiac isoform of TRDN (NM_001256021.1; Kobayashi YM et al. J. Biol. Chem., 1999 Oct;274:28660-8). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV002528268 SCV003022584 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2022-02-08 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 22 of the TRDN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TRDN cause disease. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with TRDN-related conditions. ClinVar contains an entry for this variant (Variation ID: 452344). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

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