Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000484114 | SCV000574076 | uncertain significance | not provided | 2017-03-16 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the DSP gene. The I2078T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I2078T 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. This substitution occurs at a position where only amino acids with similar properties to isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. |
Color Diagnostics, |
RCV001180114 | SCV001344977 | uncertain significance | Cardiomyopathy | 2023-04-05 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with threonine at codon 2078 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 dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 5/251142 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. |
Labcorp Genetics |
RCV001219465 | SCV001391406 | likely benign | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 | 2024-02-01 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV002481540 | SCV002777323 | 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 | 2021-08-27 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV003168984 | SCV003855683 | uncertain significance | Cardiovascular phenotype | 2023-03-13 | criteria provided, single submitter | clinical testing | The p.I2078T variant (also known as c.6233T>C), located in coding exon 24 of the DSP gene, results from a T to C substitution at nucleotide position 6233. The isoleucine at codon 2078 is replaced by threonine, an amino acid with similar properties. This variant has been detected in an individual from a dilated cardiomyopathy cohort and in an individual without reported cardiovascular disease; however, clinical details were limited (Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487; Wei X et al. PLoS One, 2011 Dec;6:e29500). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003993981 | SCV004814026 | uncertain significance | not specified | 2024-02-20 | criteria provided, single submitter | clinical testing | Variant summary: DSP c.6233T>C (p.Ile2078Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251142 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6233T>C has been reported in the literature in one individual affected with Dilated Cardiomyopathy (Verdonschot_2020), without strong evidence for causality. 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. The following publication have been ascertained in the context of this evaluation (PMID: 32880476). ClinVar contains an entry for this variant (Variation ID: 424285). Based on the evidence outlined above, the variant was classified as uncertain significance. |
All of Us Research Program, |
RCV004003407 | SCV004825415 | uncertain significance | Arrhythmogenic cardiomyopathy with wooly hair and keratoderma | 2024-05-17 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with threonine at codon 2078 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 dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 5/251142 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. |