Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000038113 | SCV000061779 | uncertain significance | not specified | 2012-06-30 | criteria provided, single submitter | clinical testing | The Arg2846Gly variant in DSP has not been reported in the literature, but has b een listed in the ARVC Mutation Database (http://arvcdatabase.info/) without any additional information. Computational analyses (biochemical amino acid properti es, conservation, AlignGVGD, and PolyPhen2) suggest that it may impact the prote in, though this information is not predictive enough to determine pathogenicity. The variant has not been detected in 2 very large and broad populations (Europe an and African American) screened by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/). This low frequency is consistent with a pathogenic role but is insufficient to establish this with confidence. Additional informat ion is needed to fully assess the clinical significance of the Arg2846Gly varian t. |
| Gene |
RCV000658263 | SCV000780034 | uncertain significance | not provided | 2018-05-24 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the DSP gene. The R2846G variant has been reported in one individual in association with ARVC, although no further clinical details or segregation studies were described (Adler et al., 2016). This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R2846G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, this variant has not been observed in a significant number of affected individuals, and it lacks both segregation and functional studies which would further clarify its pathogenicity. Finally, R2846G is also classified as a variant of uncertain significance in ClinVar by another clinical laboratory (SCV000061779.5; Landrum et al., 2016). |
| Invitae | RCV001050089 | SCV001214177 | likely benign | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 | 2023-05-13 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV001183718 | SCV001349527 | uncertain significance | Cardiomyopathy | 2023-02-09 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glycine at codon 2846 of the DSP 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 DSP-related disorders in the literature. This variant has been identified in 2/278452 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. |
| Fulgent Genetics, |
RCV002490519 | SCV002779155 | uncertain significance | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis | 2021-09-13 | criteria provided, single submitter | clinical testing |