ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2774G>A (p.Arg925Gln) (rs139799237)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181307 SCV000233600 uncertain significance not specified 2015-11-06 criteria provided, single submitter clinical testing p.Arg925Gln (R925Q) CGG>CAG: c.2774 G>A in exon 19 of the DSP gene (NM_004415.2). The R925Q variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R925Q variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R925Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, mutations in nearby residues have not been reported in association with ARVC, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARVC panel(s).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000181307 SCV000271723 uncertain significance not specified 2015-03-18 criteria provided, single submitter clinical testing The p.Arg925Gln variant in DSP has not been previously reported in individuals w ith cardiomyopathy, but has been identified in up to 0.2% of chromosomes (13/667 32) from multiple ethnic groups curated by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs139799237). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg925Gln variant is uncertain.
Illumina Clinical Services Laboratory,Illumina RCV000291383 SCV000464958 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000327634 SCV000464959 likely benign Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000377986 SCV000464960 likely benign Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000283495 SCV000464961 likely benign Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000456401 SCV000543281 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 925 of the DSP protein (p.Arg925Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs139799237, ExAC 0.05%). This variant has been reported in an individual affected with  arrhythmogenic right ventricular cardiomyopathy and in an individual referred for testing for inherited arrhythmia (PMID: 26383259, 26743238). ClinVar contains an entry for this variant (Variation ID: 199875). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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 RCV000621213 SCV000734918 uncertain significance Cardiovascular phenotype 2017-07-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000777766 SCV000913734 uncertain significance Cardiomyopathy 2018-10-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the plakin domain of the DSP protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual referred for a possible primary electric syndrome or arrhythmogenic right ventricular cardiomyopathy (PMID: 26743238). This variant has also been identified in 64/277128 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Klaassen Lab,Charite University Medicine Berlin RCV000853132 SCV000995844 uncertain significance Familial restrictive cardiomyopathy 2019-07-03 criteria provided, single submitter research

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