Submissions for variant NM_001943.5(DSG2):c.1964A>T (p.His655Leu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002423363	SCV002721467	uncertain significance	Cardiovascular phenotype	2018-09-27	criteria provided, single submitter	clinical testing	The p.H655L variant (also known as c.1964A>T), located in coding exon 13 of the DSG2 gene, results from an A to T substitution at nucleotide position 1964. The histidine at codon 655 is replaced by leucine, an amino acid with similar properties. This amino acid position is well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003097395	SCV003461120	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2022-12-04	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. This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 655 of the DSG2 protein (p.His655Leu).
All of Us Research Program, National Institutes of Health	RCV004007383	SCV004819593	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 655 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 reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.