Submissions for variant NM_001943.5(DSG2):c.1520G>A (p.Cys507Tyr)

gnomAD frequency: 0.00001  dbSNP: rs121913009

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001178344	SCV001342755	uncertain significance	Cardiomyopathy	2023-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 507 of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16773573, 20152563, 23871885, 31737537). This variant has been identified in 2/280834 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	RCV000018306	SCV001395117	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-04-18	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 16813). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 20031617, 20152563, 31737537). This variant is present in population databases (rs121913009, gnomAD 0.01%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 507 of the DSG2 protein (p.Cys507Tyr).
GeneDx	RCV001588816	SCV001824069	uncertain significance	not provided	2023-08-07	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16773573, 20152563, 20857253, 20031617, 23671136, 23871885, 31737537, 31402444, 32665702)
Ambry Genetics	RCV002390115	SCV002705311	uncertain significance	Cardiovascular phenotype	2021-05-28	criteria provided, single submitter	clinical testing	The p.C507Y variant (also known as c.1520G>A), located in coding exon 11 of the DSG2 gene, results from a G to A substitution at nucleotide position 1520. The cysteine at codon 507 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been detected in an individual reported to have arrhythmogenic right ventricular cardiomyopathy (ARVC) and in cases referred for ARVC genetic testing (Awad MM et al. Am. J. Hum. Genet., 2006 Jul;79:136-42 (reported as C506Y); Marschall C et al. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298). This variant has also been detected in several individuals from exome sequencing cohorts who were not know to have ARVC (Haggerty CM et al. Genet. Med., 2017 11;19:1245-1252; van Rooij J et al. Genet Med. 2020 11;22(11):1812-1820). 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	RCV002476988	SCV002784108	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2022-04-08	criteria provided, single submitter	clinical testing
OMIM	RCV000018306	SCV000038585	pathogenic	Arrhythmogenic right ventricular dysplasia 10	2006-07-01	no assertion criteria provided	literature only