Submissions for variant NM_001943.5(DSG2):c.581C>T (p.Ser194Leu)

gnomAD frequency: 0.00001  dbSNP: rs374875442

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037312	SCV000060969	uncertain significance	not specified	2016-05-27	criteria provided, single submitter	clinical testing	The p.Ser194Leu variant in DSG2 has been reported in a compound heterozygous ind ividual with ARVC (Nakajima 2012). In addition, this variant has been identified by our laboratory in one child with clinical features of DCM and ARVD/C. It has been identified in 3/16492 South Asian chromosomes by the Exome Aggregation Con sortium (ExAC, http://exac.broadinstitute.org; dbSNP rs374875442). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine path ogenicity. In summary, the clinical significance of the p.Ser194Leu variant is u ncertain.
Invitae	RCV000642313	SCV000763982	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-07-18	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 44324). This missense change has been observed in individual(s) with clinical features of DSG2-related conditions (PMID: 22214898, 33500567). This variant is present in population databases (rs374875442, gnomAD 0.02%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 194 of the DSG2 protein (p.Ser194Leu).
GeneDx	RCV001560109	SCV001782450	uncertain significance	not provided	2019-10-25	criteria provided, single submitter	clinical testing	Reported with a different missense variant on the opposite allele (in trans) in an individual with ARVC, and observed in apparent homozygous state in another individual with ARVC in published literature (Nakajima et al., 2012; Shapieva et al., 2014); in one family, S194L segregated in an unaffected relative and a relative whose echocardiogram showed a minor right ventricular structural abnormality, but their EKG was not suggestive of ARVC (Nakajima et al., 2012); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 44324; Landrum et al., 2016), and one clinical laboratory identified this variant in a child with clinical features of DCM and ARVC (SCV000060969.4; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30177324, 22214898, 23299917)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037312	SCV002511640	uncertain significance	not specified	2022-04-11	criteria provided, single submitter	clinical testing	Variant summary: DSG2 c.581C>T (p.Ser194Leu) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249350 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.581C>T has been reported in the literature in compound heterozygosity with another DSG2 variant in an individual with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVC) (example, Nakajima_2012). Her asymptomatic sibling and mother carried this variant. A minor structural abnormality was noted upon echocardiographic examination of the mother. The authors suggested that this variant alone may not be sufficiently penetrant to cause ARVC. Since this report, it has also been reported in one case of left ventricular noncompaction (LVNC) (example, Mazzarotto_2021). These report(s) 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002482987	SCV002792838	uncertain significance	Arrhythmogenic right ventricular dysplasia 10; Dilated cardiomyopathy 1BB	2021-07-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162323	SCV003858254	uncertain significance	Cardiovascular phenotype	2022-12-16	criteria provided, single submitter	clinical testing	The p.S194L variant (also known as c.581C>T), located in coding exon 6 of the DSG2 gene, results from a C to T substitution at nucleotide position 581. The serine at codon 194 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts; however, clinical details were limited and additional alterations in other ARVC-related genes were identified in one case (Nakajima T et al. Circ J, 2012 Dec;76:737-43; Ren C et al. Medicine (Baltimore), 2020 Jun;99:e20279). Additionally, this alteration was detected in a left ventricular non-compaction (LVNC) cohort; however, clinical details were also limited (Mazzarotto F et al. Genet Med, 2021 May;23:856-864). This amino acid position is 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.