Submissions for variant NM_024422.6(DSC2):c.865C>T (p.Pro289Ser)

gnomAD frequency: 0.00002  dbSNP: rs200802591

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039443	SCV000063127	uncertain significance	not specified	2010-12-14	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Pro289Ser v ariant has been reported in one individual with possible ARVD/C and was absent f rom 300 ethnically matched control chromosomes (Bhuiyan 2009). Proline (Pro) at position 289 is conserved across in mammals (more distant species were not avail able. In addition, three computer programs (AlignGCGD, PolyPhen, SIFT) predict t he variant to significantly affect the protein?s function. While the absence fro m controls and the limited evolutionary conservation data available support a pa thogenic role, the number of controls tested is not high enough to exclude that the variant is benign. In summary, the significance of the Pro289Ser variant c annot be determined without additional studies.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000608268	SCV000743497	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2017-01-25	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000608268	SCV000744768	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2015-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181113	SCV001346199	uncertain significance	Cardiomyopathy	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 289 of the DSC2 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 an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 20031616) and in an individual affected with dilated cardiomyopathy (Verdonschot 2021, disertation, Maastricht University). This variant has also been identified in 8/282798 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	RCV000608268	SCV001490121	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 289 of the DSC2 protein (p.Pro289Ser). This variant is present in population databases (rs200802591, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 20031616, 30847666, 32880476). ClinVar contains an entry for this variant (Variation ID: 46200). 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 expected to disrupt DSC2 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.
GeneDx	RCV001552905	SCV001773679	uncertain significance	not provided	2019-09-30	criteria provided, single submitter	clinical testing	Reported in one Dutch individual diagnosed with probable ARVC based on Task Force Criteria (Bhuiyan et al., 2009); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#46200; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek 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: 32880476, 30847666, 20031616)
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000608268	SCV000733779	uncertain significance	Arrhythmogenic right ventricular dysplasia 11		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001552905	SCV001918893	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001552905	SCV001954078	uncertain significance	not provided		no assertion criteria provided	clinical testing