chr6-123393630-CT-AG

Position:

• chr6-123393630-CT-AG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006073.4(TRDN):​c.1098_1099inv​(p.Ala367Ser) variant causes a missense 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRDN NM_006073.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0500

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRDN	NM_006073.4	c.1098_1099inv	p.Ala367Ser	missense_variant	13/41	ENST00000334268.9	NP_006064.2
TRDN	NM_001251987.2	c.1101_1102inv	p.Ala368Ser	missense_variant	13/21		NP_001238916.1
TRDN	NM_001407315.1	c.1041_1042inv	p.Ala348Ser	missense_variant	12/20		NP_001394244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRDN	ENST00000334268.9	c.1098_1099inv	p.Ala367Ser	missense_variant	13/41	1	NM_006073.4	ENSP00000333984	A2
TRDN-AS1	ENST00000587106.6	n.55+4155_55+4156inv		intron_variant, non_coding_transcript_variant		5
TRDN	ENST00000662930.1	c.1101_1102inv	p.Ala368Ser	missense_variant	13/21			ENSP00000499585

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 03, 2022

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 659885). This variant has not been reported in the literature in individuals affected with TRDN-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 367 of the TRDN protein (p.Ala367Ser). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2022

The c.1098_1099delAGinsCT variant (also known as p.A367S), located in coding exon 13 of the TRDN gene, results from an in-frame deletion of AG and insertion of CT at nucleotide positions 1098 to 1099. This results in the substitution of the alanine residue for a serine residue at codon 367, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-123714775;