Submissions for variant NM_001943.5(DSG2):c.1297G>T (p.Asp433Tyr)

dbSNP: rs938919152

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000619981	SCV000734880	uncertain significance	Cardiovascular phenotype	2023-12-07	criteria provided, single submitter	clinical testing	The p.D433Y variant (also known as c.1297G>T), located in coding exon 10 of the DSG2 gene, results from a G to T substitution at nucleotide position 1297. The aspartic acid at codon 433 is replaced by tyrosine, an amino acid with highly dissimilar properties. 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 variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000772656	SCV000905915	uncertain significance	Cardiomyopathy	2023-10-18	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 433 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003517251	SCV004317739	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-08-16	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 518464). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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 aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 433 of the DSG2 protein (p.Asp433Tyr).
All of Us Research Program, National Institutes of Health	RCV004002636	SCV004819527	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-11-02	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the extracellular cadherin domain 4 of the DSG2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.