ClinVar Miner

Submissions for variant NM_006073.4(TRDN):c.1537+1G>A

gnomAD frequency: 0.00019  dbSNP: rs189125299
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002523314 SCV000548528 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2024-12-06 criteria provided, single submitter clinical testing This sequence change falls in intron 25 of the TRDN gene. It does not directly change the encoded amino acid sequence of the TRDN protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs189125299, gnomAD 0.08%), including at least one homozygous and/or hemizygous individual. 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: 408727). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
GeneDx RCV000497346 SCV000590699 uncertain significance not provided 2021-05-26 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV000618646 SCV000737653 uncertain significance Cardiovascular phenotype 2024-09-18 criteria provided, single submitter clinical testing The c.1537+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 25 of the TRDN gene. This nucleotide position is well 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.
AiLife Diagnostics, AiLife Diagnostics RCV000497346 SCV002501753 uncertain significance not provided 2021-07-22 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002506123 SCV002815545 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1; Catecholaminergic polymorphic ventricular tachycardia 5 2022-04-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003993969 SCV004812964 uncertain significance not specified 2024-02-27 criteria provided, single submitter clinical testing Variant summary: TRDN c.1537+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, the main TRDN isoform expressed in the heart (NM_001256021.1) is not impacted by this alteration and these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 245594 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in TRDN causing Catecholaminergic Polymorphic Ventricular Tachycardia (0.00014 vs 0.0016), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1537+1G>A in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 408727). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breakthrough Genomics, Breakthrough Genomics RCV000497346 SCV005189224 uncertain significance not provided criteria provided, single submitter not provided

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