Submissions for variant NM_001943.5(DSG2):c.1281A>T (p.Arg427Ser)

gnomAD frequency: 0.00001  dbSNP: rs370547219

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487007	SCV000567828	uncertain significance	not provided	2020-09-02	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV001176568	SCV001340588	uncertain significance	Cardiomyopathy	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 427 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function. 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 2/236004 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204581	SCV001375794	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-05-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 427 of the DSG2 protein (p.Arg427Ser). This variant is present in population databases (rs370547219, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 419778). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV002383920	SCV002695281	uncertain significance	Cardiovascular phenotype	2022-10-02	criteria provided, single submitter	clinical testing	The p.R427S variant (also known as c.1281A>T) is located in coding exon 10 of the DSG2 gene. The arginine at codon 427 is replaced by serine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 10. This amino acid position is conserved. 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	RCV004002315	SCV004819525	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-07-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 427 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/236004 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.
Molecular Genetics, Royal Melbourne Hospital	RCV004002315	SCV005900503	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-12-06	criteria provided, single submitter	clinical testing	This sequence change in DSG2 is predicted to replace arginine with serine at codon 427, p.(Arg427Ser). This nucleotide position corresponds to the first coding base of exon 10. The arginine residue is weakly conserved (100 vertebrates, Multiz Alignments), and is located in the 4th extracellular cadherin domain. There is a large physicochemical difference between arginine and serine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.002% (20/1,149,772 alleles) in the European Non-Finnish population, which is consistent with dominant disease. ClinVar contains an entry for this variant (Variation ID: 419778). This variant has been reported in one proband with arrhythmogenic cardiomyopathy (PMID: 38691546). Computational evidence predicts a benign effect for the missense substitution (REVEL = 0.07). However, this variant is may activate a cryptic exonic acceptor site (SpliceAI = 0.27). RNA assays have not been conducted to confirm this prediction. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3.