Variant chr6-123512344-A-AT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_006073.4(TRDN):c.568_569insA(p.Ile190AsnfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TRDN
NM_006073.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -0.0100

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 6-123512344-A-AT is Pathogenic according to our data. Variant chr6-123512344-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225497.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 linkuse as main transcript	c.568_569insA	p.Ile190AsnfsTer2	frameshift_variant	7/41	ENST00000334268.9	NP_006064.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.568_569insA	p.Ile190AsnfsTer2	frameshift_variant	7/41	1	NM_006073.4	ENSP00000333984	A2	Q13061-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1353066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

672998

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Feb 02, 2018

Variant TRDN, Exon 7, p.Ile190Asnfs*2 (c.568dupA) NM_001251987.1 chr6-123833490--T SCICD classification Likely pathogenic (for recessive disease) We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: type of variant in this gene likely to be pathogenic, sufficiently rare. Gene-level evidence TRDN variants are newly recognized as a cause of autosomal recessive arrhythmic syndromes resembling CPVT and long QT syndrome. Several of the reported pathogenic variants are nonsense, frameshift, or splice. As far as we are aware phenotype in heterozygotes has not been reported. Case data summary Per lab report and my searches, variant has not been reported with disease. Population Data There is no variation at this genomic position in gnomAD. Metrics indicate adequate coverage. -

Catecholaminergic polymorphic ventricular tachycardia 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TRDN are known to be pathogenic (PMID: 25922419). This variant has not been reported in the literature in individuals with TRDN-related disease. ClinVar contains an entry for this variant (Variation ID: 225497). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ile190Asnfs*2) in the TRDN gene. It is expected to result in an absent or disrupted protein product. -

Catecholaminergic polymorphic ventricular tachycardia 5

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over