Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000807576 | SCV000947638 | uncertain significance | Arrhythmogenic right ventricular dysplasia 10 | 2023-06-21 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 652087). This missense change has been observed in individual(s) with arrythmogenic right ventricular cardiomyopathy (ARVC) and a definite or borderline diagnosis of ARVC (PMID: 21606390, 22036071). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 333 of the DSG2 protein (p.Ile333Thr). |
Ambry Genetics | RCV002381783 | SCV002689656 | uncertain significance | Cardiovascular phenotype | 2024-04-16 | criteria provided, single submitter | clinical testing | The p.I333T variant (also known as c.998T>C), located in coding exon 8 of the DSG2 gene, results from a T to C substitution at nucleotide position 998. The isoleucine at codon 333 is replaced by threonine, an amino acid with similar properties. This variant co-occurred with another DSG2 alteration in trans in a proband with arrhythmogenic right ventricular cardiomyopathy (ARVC). The proband's mother with only DSG2 p.I333T was reportedly unaffected (Gehmlich K et al. Cardiovasc. Pathol. Oct;21:275-82). This alteration was also reported in a proband with ARVC who also carried a second alteration in DSG2 (Vischer AS et al. Int J Cardiol, 2019 Jul;286:99-103). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |