chr6-123393624-C-T

Position:

chr6-123393624-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006073.4(TRDN):c.1105G>A(p.Ala369Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,602,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TRDN
NM_006073.4 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.24

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:

TRDN-AS1 (HGNC:40592): (TRDN antisense RNA 1)

TRDN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TRDN	NM_006073.4 linkuse as main transcript	c.1105G>A	p.Ala369Thr	missense_variant, splice_region_variant	13/41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2 linkuse as main transcript	c.1108G>A	p.Ala370Thr	missense_variant, splice_region_variant	13/21		NP_001238916.1
TRDN	NM_001407315.1 linkuse as main transcript	c.1048G>A	p.Ala350Thr	missense_variant, splice_region_variant	12/20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9 linkuse as main transcript	c.1105G>A	p.Ala369Thr	missense_variant, splice_region_variant	13/41	1	NM_006073.4	ENSP00000333984	A2	Q13061-1
TRDN-AS1	ENST00000587106.6 linkuse as main transcript	n.55+4149C>T		intron_variant, non_coding_transcript_variant		5
TRDN	ENST00000662930.1 linkuse as main transcript	c.1108G>A	p.Ala370Thr	missense_variant, splice_region_variant	13/21			ENSP00000499585

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000300

AC:

AN:

233000

Hom.:

AF XY:

0.0000159

AC XY:

AN XY:

126106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000105

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000577

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000110

AC:

160

AN:

1450204

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

720378

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000389

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000129

Gnomad4 OTH exome

AF:

0.000268

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151976

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000957

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2024

Not observed at significant frequency in large population cohorts (gnomAD); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site but the effect on protein function is unclear; In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32579932) -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 19, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 369 of the TRDN protein (p.Ala369Thr). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is present in population databases (rs369198088, gnomAD 0.01%). 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: 408726). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2023

The c.1105G>A variant (also known as p.A369T), located in coding exon 13 of the TRDN gene, results from a G to A substitution at nucleotide position 1105. The amino acid change results in alanine to threonine at codon 369, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 13, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. 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

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 23, 2021

The TRDN c.1105G>A; p.Ala369Thr variant (rs369198088), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 408726). This variant is found on only eight chromosomes (8/264396 alleles) in the Genome Aggregation Database. The alanine at codon 396 is moderately conserved, and computational analyses predict that this variant is neutral (REVEL: 0.057). However, this variant also occurs in the last nucleotide of exon 13, and computational analyses of splicing (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, although RNA studies would be required to confirm this. Given the lack of clinical and functional data, the significance of the p.Ala369Thr variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.54

M_CAP

Benign

0.018

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

MutationTaster

Benign

0.90

D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.12

REVEL

Benign

0.057

Sift

Pathogenic

0.0

Sift4G

Benign

0.53

Polyphen

0.99

Vest4

0.18

MVP

0.30

ClinPred

0.25

GERP RS

5.2

Varity_R

0.18

gMVP

0.012

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.66

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.66

Position offset: 0

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