Submissions for variant NM_001943.5(DSG2):c.1397C>T (p.Thr466Ile)

gnomAD frequency: 0.00007  dbSNP: rs769137357

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485460	SCV000571941	uncertain significance	not provided	2016-10-25	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DSG2 gene. The T466I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T466I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species and where Isoleucine is the wild type the opossum. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV000642322	SCV000763991	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 466 of the DSG2 protein (p.Thr466Ile). This variant is present in population databases (rs769137357, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 422458). 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 DSG2 protein function with a negative predictive value of 95%. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171306	SCV001334034	uncertain significance	Cardiomyopathy	2018-05-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171306	SCV001351115	uncertain significance	Cardiomyopathy	2021-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 466 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with arrhythmogenic cardiomyopathy (PMID: 28254189). This variant has been identified in 4/279646 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002395171	SCV002697134	uncertain significance	Cardiovascular phenotype	2021-05-26	criteria provided, single submitter	clinical testing	The p.T466I variant (also known as c.1397C>T), located in coding exon 10 of the DSG2 gene, results from a C to T substitution at nucleotide position 1397. The threonine at codon 466 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in a subject with arrhythmogenic cardiomyopathy (ACM), who also carried a missense variant in HCN4 (Schweizer PA et al. J Am Coll Cardiol, 2017 03;69:1209-1210). This amino acid position is well conserved in available vertebrate species; however, isoleucine is the reference amino acid in other 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.
Fulgent Genetics, Fulgent Genetics	RCV002475941	SCV002792658	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-10-11	criteria provided, single submitter	clinical testing