Submissions for variant NM_001943.5(DSG2):c.46A>G (p.Ile16Val)

gnomAD frequency: 0.00001  dbSNP: rs376660601

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489115	SCV000576795	uncertain significance	not provided	2017-04-19	criteria provided, single submitter	clinical testing	The I16V variant has not been published as pathogenic or been reported as benign to our knowledge. It is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position where only amino acids with similar properties to isoleucine (I) are tolerated across species. However, the I16V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064778	SCV001229698	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2022-01-26	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 426374). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This variant is present in population databases (rs376660601, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 16 of the DSG2 protein (p.Ile16Val).
Color Diagnostics, LLC DBA Color Health	RCV001184828	SCV001350905	uncertain significance	Cardiomyopathy	2023-07-31	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 16 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 DSG2-related disorders in the literature. This variant has been identified in 1/249316 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	RCV002341154	SCV002636391	uncertain significance	Cardiovascular phenotype	2018-05-11	criteria provided, single submitter	clinical testing	The p.I16V variant (also known as c.46A>G) is located in coding exon 2 of the DSG2 gene. The isoleucine at codon 16 is replaced by valine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 2. This amino acid position is not well conserved in available vertebrate species, and valine 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.
All of Us Research Program, National Institutes of Health	RCV004806370	SCV005427550	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 16 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 been identified in 1/249316 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.