Submissions for variant NM_001943.5(DSG2):c.1592T>G (p.Phe531Cys)

gnomAD frequency: 0.00001  dbSNP: rs200484060

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000168632	SCV000050858	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2018-04-05	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037268	SCV000060925	uncertain significance	not specified	2011-12-23	criteria provided, single submitter	clinical testing	The Phe531Cys variant (DSG2) has been reported as a homozygous variant in one Ta wainese individual with ARVD and was absent in 200 control chromosomes (Yu 2008) . Phenylalanine (Phe) at position 531 is highly conserved across evolutionarily distant species, increasing the likelihood that a change would not be tolerated. Computational tools are mixed on the predicted impact to the protein (PolyPhen 2 & SIFT = pathogenic, AlignGVGD = benign), though the accuracy of these tools i s unknown. In summary, the clinical significance of this variant cannot be deter mined at this time.
GeneDx	RCV000766865	SCV000616700	uncertain significance	not provided	2018-06-28	criteria provided, single submitter	clinical testing	The F531C variant of uncertain significance in the DSG2 gene has been previously reported in either the heterozygous or homozygous state in several Asian individuals with definite or suspected ARVC (Yu et al., 2008; Bao et al., 2013a; Bao et al., 2013b; Ohno et al., 2013); however, detailed clinical information and segregation data were not provided for most probands. In addition, one of these probands, who inherited the F531C variant from his father, was also found to be homozygous for a second variant in the DSP gene (Ohno et al., 2013). Upon evaluation, both of his parents were diagnosed with possible ARVC and were found to be heterozygous for this DSP variant (Ohno et al., 2013). Furthermore, F531C has been identified in the homozygous state in two other individuals referred for cardiac genetic testing at GeneDx. This variant has also been observed in approximately 0.1% of alleles from individuals of East Asian background in the Exome Aggregation Consortium, indicating it may be a rare benign variant in this population (Lek et al., 2016; Exome Variant Server). Nevertheless, F531C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution also occurs at a position that is conserved across species. Moreover, in silico analysis predicts F531C is probably damaging to the protein structure/function.
Invitae	RCV001034635	SCV000820753	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 531 of the DSG2 protein (p.Phe531Cys). This variant is present in population databases (rs200484060, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 18632414, 23514727, 24238504, 25765472, 28578331, 28878402, 30454721, 30830208, 31645976). ClinVar contains an entry for this variant (Variation ID: 44283). 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. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171307	SCV001334036	uncertain significance	Cardiomyopathy	2018-03-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171307	SCV001349853	uncertain significance	Cardiomyopathy	2022-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with cysteine at codon 531 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). A study using a homozygous knock-in mouse model has reported that this variant results in a cardiomyopathy phenotype with left ventricular systolic dysfunction (Wang et. al, 2019). This variant has been reported in over ten individuals of East Asian ancestry affected with arrhythmogenic right ventricular cardiomyopathy, either in homozygous or compound heterozygous state (PMID: 18632414, 23514727, 24125834, 25765472, 28578331, 30129429, 30177324, 30454721, 31183845, 31645976; Wang et. al, 2019, https://doi.org/10.1093/eurheartj/ehz746.0202). In these families, over 20 heterozygous family members were reported to be unaffected, while several heterozygotes were reported to be affected with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, or sudden unexplained death. This variant has also been identified in 16/280790 chromosomes (16/19518 East Asian chromosomes, 0.0819%) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in autosomal dominant arrhythmogenic cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.