ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.998T>C (p.Ile333Thr)

gnomAD frequency: 0.00001  dbSNP: rs773871942
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae 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 2019-12-16 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 amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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