ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.242G>A (p.Cys81Tyr) (rs140965835)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038009 SCV000061675 uncertain significance not specified 2018-04-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000766871 SCV000233557 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing The C81Y variant of uncertain significance in the DSP gene was initially reported in a Danish male diagnosed with ARVC; however, it was also detected in 2/1,400 controls (Christensen et al., 2010). In addition, this individual harbored a canonical splice site variant in the PKP2 gene, which was also identified in an affected sibling who did not harbor the C81Y variant (Christensen et al., 2010). Visser et al. (2017) identified C81Y in a Dutch individual with idiopathic ventricular fibrillation who had no signs of structural cardiac disease after 12 years of follow-up. This variant was also identified in a patient with conduction disease who harbored additional variants in the TRMP4 and HCN4 genes (Arbustini et al., 2017).The C81Y variant is classified in ClinVar as a variant of uncertain significance by other clinical laboratories, one of which noted lack of segregation with DCM in an affected relative (SCV000061675.4, SCV000543280.1; Landrum et al., 2016). This variant has been observed, both independently and in conjunction with additional variants, in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, but thus far, segregation studies have been non-informative. The C81Y variant is observed in 34/126,588 alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). C81Y 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000470962 SCV000543280 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-10-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 81 of the DSP protein (p.Cys81Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs140965835, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy, who also carried the PKP2 c.2146-2A>T variant, and this variant has been found in 2/1400 unaffected controls (PMID: 20864495). Additionally, this variant has been described in individuals affected with idiopathic ventricular fibrillation (PMID: 28087426), left ventricular noncompaction or left ventricular hypertrabeculation (PMID: 28798025), and in an individual with conduction disease, who also carried other variants in HCN4 and TRPM4 (PMID: 28254189). ClinVar contains an entry for this variant (Variation ID: 44875). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
CSER _CC_NCGL, University of Washington RCV000590870 SCV000700091 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770229 SCV000901660 uncertain significance Cardiomyopathy 2017-04-21 criteria provided, single submitter clinical testing
Color RCV000770229 SCV000914072 uncertain significance Cardiomyopathy 2018-05-11 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the DSP protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been identified in an individual with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495) along with a PKP2 c.2146-2A>T splice site variant. However, only the splice site variant was found in the proband's clinically affected younger brother. This variant has been identified in 42/277042 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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