Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV001524569 | SCV001734464 | uncertain significance | Cardiomyopathy | 2021-12-16 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with isoleucine at codon 1462 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with idiopathic restrictive cardiomyopathy (PMID: 27662471, 28831623). 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. |
| Gene |
RCV001559565 | SCV001781818 | uncertain significance | not provided | 2019-08-23 | criteria provided, single submitter | clinical testing | Although this indel variant has not been published to our knowledge, a single nucleotide substitution (c.4385G>T) causing the same S1462I missense change has been reported in a pediatric patient with restrictive cardiomyopathy, arrhythmia and myopathy in published literature (Kostareva et al., 2016); however, additional variants in other genes were also identified and no segregation data are available; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28831623, 27662471) |
| Fulgent Genetics, |
RCV002498776 | SCV002784087 | 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 | 2021-08-20 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002516354 | SCV003252296 | uncertain significance | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 | 2023-11-13 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1462 of the DSP protein (p.Ser1462Ile). This variant is present in population databases (rs730880090, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 180341). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |
| Ambry Genetics | RCV003362697 | SCV004079949 | uncertain significance | Cardiovascular phenotype | 2023-07-14 | criteria provided, single submitter | clinical testing | The c.4385_4386delGCinsTT variant (also known as p.S1462I), located in coding exon 23 of the DSP gene, results from an in-frame deletion of GC and insertion of TT at nucleotide positions 4385 to 4386. This results in the substitution of the serine residue for an isoleucine residue at codon 1462, an amino acid with dissimilar properties. Based on data from gnomAD, this allele has an overall frequency of 0.0036%% (9/251138) total alleles studied. The highest observed frequency was 0.0079% (9/113462) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Blueprint Genetics | RCV000157214 | SCV000206938 | uncertain significance | Restrictive cardiomyopathy; Long QT syndrome | 2014-06-24 | no assertion criteria provided | clinical testing |