NM_006073.4(TRDN):c.22+29A>G AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 26, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002432068.8

Allele description [Variation Report for NM_006073.4(TRDN):c.22+29A>G]

NM_006073.4(TRDN):c.22+29A>G

Gene:

TRDN:triadin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q22.31

Genomic location:

Preferred name:

NM_006073.4(TRDN):c.22+29A>G

HGVS:

NC_000006.12:g.123636725T>C
NG_030438.1:g.5369A>G
NM_001251987.2:c.22+29A>G
NM_001256020.2:c.22+29A>G
NM_001256021.2:c.22+29A>G
NM_001256022.2:c.22+29A>G
NM_006073.4:c.22+29A>GMANE SELECT
NC_000006.11:g.123957870T>C
NM_001256021.1:c.22+29A>G
NM_006073.2:c.22+29A>G
NM_006073.4:c.22+29A>G

Nucleotide change:

IVS1, A-G, +29

Links:

OMIM: 603283.0005; dbSNP: rs774068079

NCBI 1000 Genomes Browser:

rs774068079

Molecular consequence:

NM_001251987.2:c.22+29A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001256020.2:c.22+29A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001256021.2:c.22+29A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001256022.2:c.22+29A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_006073.4:c.22+29A>G - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002727486	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Jul 26, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25922419, 26200674 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002727486

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Jul 26, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest: Elucidation of the Triadin Knockout Syndrome.

Altmann HM, Tester DJ, Will ML, Middha S, Evans JM, Eckloff BW, Ackerman MJ.

Circulation. 2015 Jun 9;131(23):2051-60. doi: 10.1161/CIRCULATIONAHA.115.015397. Epub 2015 Apr 28.

PubMed [citation]

PMID:: 25922419

New Family With Catecholaminergic Polymorphic Ventricular Tachycardia Linked to the Triadin Gene.

Rooryck C, Kyndt F, Bozon D, Roux-Buisson N, Sacher F, Probst V, Thambo JB.

J Cardiovasc Electrophysiol. 2015 Oct;26(10):1146-50. doi: 10.1111/jce.12763. Epub 2015 Sep 1.

PubMed [citation]

PMID:: 26200674

Details of each submission

From Ambry Genetics, SCV002727486.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

The c.22+29A>G intronic pathogenic mutation results from an A to G substitution 29 nucleotides after coding exon 1 in the TRDN gene. This mutation has been reported to be in trans with the TRDN truncating mutation p.Q205* in three siblings, two of whom were diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT). An in vitro minigene assay revealed that the mutation causes abnormal splicing, leading to inclusion of 29 nucleotides from intron 1 and hence a frameshift with a predicted alternate stop codon (p.N9Ifs*7) (Rooryck C et al. J. Cardiovasc. Electrophysiol. 2015;26:1146-50). This alteration has also been detected in trans with a TRDN frameshift mutation (c.438-442delTAAGA) in a patient presenting with fetal bradycardia and possible long QT syndrome progressing to ventricular fibrillation in childhood, with some ECG findings suggestive of CPVT, as well as decreased skeletal muscle strength and tone at four years of age (Altmann HM et al. Circulation, 2015;131:2051-60). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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