Submissions for variant NM_001943.5(DSG2):c.430G>A (p.Glu144Lys)

gnomAD frequency: 0.00014  dbSNP: rs199842209

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171897	SCV000050910	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000171897	SCV000233482	uncertain significance	not provided	2023-03-22	criteria provided, single submitter	clinical testing	Identified in patients with ARVC in published literature (Bidina et al., 2018; Marschall et al., 2019); however, it has been described as a benign variant; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23861362, 26582918, 30391969, 31737537)
Ambry Genetics	RCV000620333	SCV000736921	uncertain significance	Cardiovascular phenotype	2023-08-15	criteria provided, single submitter	clinical testing	The p.E144K variant (also known as c.430G>A), located in coding exon 5 of the DSG2 gene, results from a G to A substitution at nucleotide position 430. The glutamic acid at codon 144 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts; however, clinical details were limited (Bidina L et al. Anatol J Cardiol, 2018 Nov;20:296-302; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000778025	SCV000914136	uncertain significance	Cardiomyopathy	2023-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 144 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30391969, 31737537), and in an exome sequencing participant not selected for arrhythmia, cardiomyopathy, or a family history of sudden death (PMID: 23861362). This variant has been identified in 26/280688 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	RCV000810288	SCV000950481	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 144 of the DSG2 protein (p.Glu144Lys). This variant is present in population databases (rs199842209, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 30391969, 31737537). ClinVar contains an entry for this variant (Variation ID: 191626). 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) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281994	SCV002571806	uncertain significance	not specified	2022-08-06	criteria provided, single submitter	clinical testing	Variant summary: DSG2 c.430G>A (p.Glu144Lys) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four out of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 249328 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (5.6e-05 vs 0.00025), allowing no conclusion about variant significance. c.430G>A has been reported in the literature in individuals with a cardiac related conditions however it was described as VUS and benign (examples: Ng_2013, Han_2014, Bidina_2018 and Marschall_2019). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002505237	SCV002816584	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-11-20	criteria provided, single submitter	clinical testing