Genetic Variant NM_006073.4:c.1900_1903delGAAA (chr6-123255869-TTTTC-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: 2.60

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRDN	NM_006073.4 link	c.1900_1903delGAAA	p.Glu634LysfsTer14	frameshift_variant	Exon 36 of 41	ENST00000334268.9	NP_006064.2	Q13061-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 link	c.1900_1903delGAAA	p.Glu634LysfsTer14	frameshift_variant	Exon 36 of 41	1	NM_006073.4	ENSP00000333984.5		Q13061-1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000138

AC:

AN:

72726

Hom.:

AF XY:

0.0000247

AC XY:

AN XY:

40416

show subpopulations

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 SAS 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:

AN:

1204532

Hom.:

AF XY:

0.0000118

AC XY:

AN XY:

591938

show subpopulations

Gnomad4 AFR exome

AF:

0.000560

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:

0.0000409

GnomAD4 genome

AF:

0.000243

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.000893

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000321

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Jul 18, 2023

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

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

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