rs545032318

Positions:

• chr6-123516189-C-A
• chr6-123516189-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006073.4(TRDN):​c.502G>T​(p.Glu168Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000203 in 1,332,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: TRDN NM_006073.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.03

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-123516189-C-A is Pathogenic according to our data. Variant chr6-123516189-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 838068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4	c.502G>T	p.Glu168Ter	stop_gained	6/41	ENST00000334268.9	NP_006064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.502G>T	p.Glu168Ter	stop_gained	6/41	1	NM_006073.4	ENSP00000333984	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000203 AC: 27 AN: 1332006 Hom.: 0 Cov.: 29 AF XY: 0.0000184 AC XY: 12 AN XY: 652602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000260

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2023	Variant summary: TRDN c.502G>T (p.Glu168X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.531del [p.Glu178fs], c.541G>T [p.Glu181Ter]). The variant was absent in 140800 control chromosomes (gnomAD). c.502G>T has been reported in the literature in compound heterozygous individuals affected with Cardiac Arrest and Ventricular Febrillation (Walsh_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classifid the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 22, 2023	This sequence change creates a premature translational stop signal (p.Glu168*) in the TRDN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRDN are known to be pathogenic (PMID: 22422768, 25922419, 26200674, 30649896). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with TRDN-related conditions (PMID: 26768964). ClinVar contains an entry for this variant (Variation ID: 838068). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The p.E168* pathogenic mutation (also known as c.502G>T), located in coding exon 6 of the TRDN gene, results from a G to T substitution at nucleotide position 502. This changes the amino acid from a glutamic acid to a stop codon within coding exon 6. This variant has co-occurred in trans with a second TRDN pathogenic variant in siblings with sudden cardiac arrest in childhood, ventricular fibrillation, prolonged or borderline QTc interval and/or bidirectional ventricular tachycardia (Walsh MA et al. Pacing Clin Electrophysiol, 2016 May;39:497-501). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Catecholaminergic polymorphic ventricular tachycardia 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.89
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Benign	0.74	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.68
ClinPred		1.0	D
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs545032318; hg19: chr6-123837334; COSMIC: COSV62121091;