Submissions for variant NM_001943.5(DSG2):c.650C>T (p.Thr217Ile)

dbSNP: rs776720174

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485181	SCV000567859	uncertain significance	not provided	2023-04-02	criteria provided, single submitter	clinical testing	Identified in at least one patient with phacomatosis pigmentovascularis (PPV) in published literature (Al-Dewik et al., 2019; Sliepka et al., 2019); Not observed at 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: 30919572, 31872050)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001070298	SCV001235520	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-06-20	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function. ClinVar contains an entry for this variant (Variation ID: 419792). This missense change has been observed in individual(s) with clinical features of DSG2-related conditions (PMID: 30919572). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 217 of the DSG2 protein (p.Thr217Ile).
Color Diagnostics, LLC DBA Color Health	RCV001176564	SCV001340584	uncertain significance	Cardiomyopathy	2022-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 217 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been reported in an individual affected with recurrent cardiorespiratory arrest and other conditions, as well as in another thirty-four individuals without personal or family history of heart disease (PMID: 34428338). This variant has not been identified 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000485181	SCV002541457	uncertain significance	not provided	2021-11-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002316	SCV004819462	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 217 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been reported in an individual affected with recurrent cardiorespiratory arrest and other conditions, as well as in another thirty-four individuals without personal or family history of heart disease (PMID: 34428338). This variant has not been identified 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.