ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1592T>G (p.Phe531Cys) (rs200484060)

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Total submissions: 6
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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, Partners HealthCare 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 cardiomyopathy, type 10 2019-09-24 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 531 of the DSG2 protein (p.Phe531Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs200484060, ExAC 0.09%). This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy, including several individuals who were homozygous for this variant (PMID: 23514727, 24238504, 25765472, 18632414, 28578331, 30454721). ClinVar contains an entry for this variant (Variation ID: 44283). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 Health, Inc RCV001171307 SCV001349853 uncertain significance Cardiomyopathy 2020-08-27 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). In a knock-in mouse model, this variant has been associated with a cardiomyopathy phenotype with left ventricular systolic dysfunction in homozygotes (Wang et. al, 2019). This variant has been reported in over 10 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). In these families, over 20 unaffected heterozygous family members of these patients were observed in addition to several heterozygotes 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). Because of the high variant allele frequency in the East Asian population, the available evidence is insufficient to determine the role of this variant in autosomal dominant arrhythmogenic right ventricular cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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