Submissions for variant NM_006073.4(TRDN):c.1801C>G (p.Pro601Ala)

gnomAD frequency: 0.00007  dbSNP: rs376214235

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222739	SCV000272545	uncertain significance	not specified	2016-03-01	criteria provided, single submitter	clinical testing	The p.Pro601Ala variant in TRDN has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/8918 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3 76214235). Computational prediction tools and conservation analysis suggest that the p.Pro601Ala variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical signif icance of the p.Pro601Ala variant is uncertain.
GeneDx	RCV000766989	SCV000619849	uncertain significance	not provided	2018-11-01	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TRDN gene. The P601A variant has not been published as pathogenic or been reported as benign to our knowledge. The P601A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P601A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved and in silico analysis predicts this variant likely does not alter the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518217	SCV000637660	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 601 of the TRDN protein (p.Pro601Ala). This variant is present in population databases (rs376214235, gnomAD 0.006%). 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: 229350). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TRDN protein function. 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.
Ambry Genetics	RCV000621140	SCV000738167	uncertain significance	Cardiovascular phenotype	2023-12-12	criteria provided, single submitter	clinical testing	The p.P601A variant (also known as c.1801C>G), located in coding exon 33 of the TRDN gene, results from a C to G substitution at nucleotide position 1801. The proline at codon 601 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV000766989	SCV001714187	uncertain significance	not provided	2020-02-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766989	SCV004162092	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TRDN: PM2, BP4