rs750469686

Variant names:

• chr6-123255869-TTTTC-T
• rs750469686
• NM_006073.4:c.1900_1903delGAAA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_006073.4(TRDN):​c.1900_1903delGAAA​(p.Glu634LysfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000383 in 1,356,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TRDN NM_006073.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 2.60
• Publications: 0 publications found

Genes affected

TRDN (HGNC:12261): (triadin) This gene encodes an integral membrane protein found in skeletal and cardiac muscle. The encoded protein plays a role in skeletal muscle excitation-contraction coupling as part of the calcium release complex and is required for normal skeletal muscle strength. This protein indirectly links triads and microtubules in skeletal muscle. Mutations in this gene are associated with cardiac arrythmia syndrome and some variants in this gene may be associated with sudden cardiac death. [provided by RefSeq, May 2022]

TRDN Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• familial long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: G2P
• long QT syndrome

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1900_1903delGAAA	p.Glu634LysfsTer14	frameshift_variant	Exon 36 of 41	ENST00000334268.9	NP_006064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1900_1903delGAAA	p.Glu634LysfsTer14	frameshift_variant	Exon 36 of 41	1	NM_006073.4	ENSP00000333984.5

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000138 AC: 1 AN: 72726 AF XY: 0.0000247

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000125 AC: 15 AN: 1204532 Hom.: 0 AF XY: 0.0000118 AC XY: 7 AN XY: 591938

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000560 AC: 13 AN: 23214

American (AMR) AF: 0.00 AC: 0 AN: 12656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19118

East Asian (EAS) AF: 0.00 AC: 0 AN: 28080

South Asian (SAS) AF: 0.00 AC: 0 AN: 53422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 971202

Other (OTH) AF: 0.0000409 AC: 2 AN: 48886

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000639755), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74342

African (AFR) AF: 0.000893 AC: 37 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000321

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Mar 06, 2017

GeneDx

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

Although the c.1900_1903delGAAA likely pathogenic variant in the TRDN gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon glutamine 634, changing it to a lysine, and creating a premature stop codon at position 14 of the new reading frame, denoted p.Glu364LysfsX14. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the TRDN gene have been reported in Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.1900_1903delGAAA variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Jan 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu634Lysfs*14) in the TRDN gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. This variant is present in population databases (rs750469686, gnomAD 0.05%). 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: 423985). 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. -

Cardiovascular phenotype Uncertain:1

Apr 30, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1900_1903delGAAA variant, located in coding exon 36 of the TRDN gene, results from a deletion of 4 nucleotides at nucleotide positions 1900 to 1903, causing a translational frameshift with a predicted alternate stop codon (p.E634Kfs*14). This alteration is expected to result in loss of function by premature protein truncation or 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. -

Catecholaminergic polymorphic ventricular tachycardia 5 Uncertain:1

Feb 13, 2023

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu634Lysfs*14 variant in the TRDN gene has not been previously reported in association with disease. This variant has been identified in 6/11,420 African/African American chromosomes (6/104,104 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Notably, allele frequency information may be unreliable as this variant is indicated to have poor coverage. This variant is present in ClinVar (Variation ID: 423985). This variant results in a 4 bp deletion in exon 36 of 41 exons, causing a shift in the protein reading frame leading to a premature termination codon 14 amino acids downstream, and is therefore predicted to undergo nonsense-mediated decay resulting in a truncated or absent protein. However, alternative splicing results in multiple tissue-specific isoforms, and the isoform mainly expressed in cardiac muscle is not predicted to be affected (Kobayashi and Jones, 1999). Loss of function is an established mechanism of disease for the TRDN gene (Altmann et al., 2015). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Glu634Lysfs*14 variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PVS1_Moderate] -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=10/190	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.31		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs750469686; hg19: chr6-123577014;