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

gnomAD frequency: 0.00005  dbSNP: rs201040643

Total submissions: 6

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 Diagnostics, LLC DBA Color Health	RCV001184545	SCV001350554	uncertain significance	Cardiomyopathy	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with isoleucine at codon 321 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals arrhythmogenic right ventricular cardiomyopathy (PMID: 28471438). This variant has been identified in 6/280820 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.
Invitae	RCV001234222	SCV001406855	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 321 of the DSG2 protein (p.Phe321Ile). This variant is present in population databases (rs201040643, gnomAD 0.005%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20152563). ClinVar contains an entry for this variant (Variation ID: 252596). 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.
Ambry Genetics	RCV002374407	SCV002690662	uncertain significance	Cardiovascular phenotype	2022-07-01	criteria provided, single submitter	clinical testing	The p.F321I variant (also known as c.961T>A), located in coding exon 8 of the DSG2 gene, results from a T to A substitution at nucleotide position 961. The phenylalanine at codon 321 is replaced by isoleucine, an amino acid with highly similar properties. This variant was reported in an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort and in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Xu T et al. J. Am. Coll. Cardiol., 2010 Feb;55:587-97; Lopes LR et al. Heart, 2015 Feb;101:294-301). This variant has also been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Haggerty CM et al. Genet. Med., 2017 11;19:1245-1252). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002503921	SCV002816012	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-08-18	criteria provided, single submitter	clinical testing