ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4775A>G (p.Lys1592Arg) (rs200421954)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000168648 SCV000233684 uncertain significance not specified 2016-12-13 criteria provided, single submitter clinical testing The Lys1592Arg variant in the DSP gene has been reported previously as an unclassified variant" in one individual diagnosed with ARVC and was absent in 400 control alleles from individuals of Dutch ancestry (Cox M et al., 2011). In addition, the Lys1592Arg variant was not detected in up to 200 alleles from individuals of African American ancestry tested at GeneDx, indicating it is not a common benign variant in this population. However, Lys1592Arg results in a conservative substitution of one positively charged amino acid for another at a residue that is not uniformly conserved across species. Furthermore, few definitive disease-causing mutations have been reported in this region of the DSP gene to date. In summary, with the clinical and molecular information available at this time, we cannot unequivocally determine if the Lys1592Arg variant is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s)."
Invitae RCV000464510 SCV000543219 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-04-30 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1592 of the DSP protein (p.Lys1592Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs200421954, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with arrhythmogenic right ventricular dysplasia (PMID: 25616645, 21606396) and unexplained sudden death (PMID:24440382). ClinVar contains an entry for this variant (Variation ID: 188466). 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 and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America RCV000586680 SCV000698437 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing Variant summary: The DSP c.4775A>G (p.Lys1592Arg) variant involves the alteration of a conserved nucleotide, which is not located in any known domain (InterPro). 4/4 in silico tools predict a benign outcome for this variant . This variant has been reported in a single patient with ARVD, and another patient with a history of syncope without conclusive evidence supportive of causality. It is observed in 22/119036 control chromosomes at a frequency of 0.0001848, which is approximately 18 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.00001), suggesting this variant is likely a benign polymorphism. Although multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, its frequency in controls suggests it is likely benign. Therefore, this variant is classified as a VUS-possibly benign.
Color RCV000778012 SCV000914122 uncertain significance Cardiomyopathy 2018-10-03 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the central rod domain of the DSP protein that is thought to form a dimeric coiled coil. 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 reported in an individual with affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606396) and in an individual with sudden death (PMID: 24440382). This variant has also been identified in 61/275966 chromosomes (46/125936 non-Finnish European 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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