ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6233T>C (p.Ile2078Thr)

gnomAD frequency: 0.00001  dbSNP: rs377035113
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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, LLC DBA Color Health 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 (formerly Invitae), Labcorp 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, 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, LabCorp 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, National Institutes of Health 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.

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