ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.961T>A (p.Phe321Ile) (rs201040643)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000238845 SCV000297110 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-10-20 criteria provided, single submitter clinical testing
GeneDx RCV000426540 SCV000520832 uncertain significance not provided 2017-04-18 criteria provided, single submitter clinical testing The F321I variant of uncertain significance in the DSG2 gene has previously been reported in one individual meeting diagnostic criteria for ARVC, however, family history and segregation data was not provided (Xu et al., 2010). This variant 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 that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge no studies have been performed to determine the functional effect of the F321I variant. Furthermore, the F321I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Color Health, Inc RCV001184545 SCV001350554 uncertain significance Cardiomyopathy 2019-05-16 criteria provided, single submitter clinical testing
Invitae RCV001234222 SCV001406855 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with isoleucine at codon 321 of the DSG2 protein (p.Phe321Ile). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and isoleucine. This variant is present in population databases (rs201040643, ExAC 0.003%). This variant has been observed in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20152563). ClinVar contains an entry for this variant (Variation ID: 252596). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). 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. 5

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