ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.889G>A (p.Asp297Asn) (rs201930322)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038117 SCV000061783 uncertain significance not specified 2012-02-22 criteria provided, single submitter clinical testing The Asp297Asn variant (DSP) has been identified in 1/7020 European American chro mosomes and 1/3738 African American chromosomes from a broad population by the N HLBI Exome sequencing project ( Aspartic acid (Asp) at position 297 is highly conserved in mammals and across evolutionarily d istant species, though computational analyses (biochemical amino acid properties , AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against a n impact to the protein. Additional information is needed to fully assess the cl inical significance of the Asp297Asn variant.
Illumina Clinical Services Laboratory,Illumina RCV000377642 SCV000464854 likely benign Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000280895 SCV000464855 likely benign Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000337806 SCV000464856 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000371415 SCV000464857 likely benign Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000467769 SCV000543274 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 297 of the DSP protein (p.Asp297Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs201930322, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 44980). 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: "Deleterious"; 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.
Color RCV000777710 SCV000913653 uncertain significance Cardiomyopathy 2018-05-21 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the spectrin repeat 4 of the plakin domain of the DSP protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact 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 nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 21/277062 chromosomes (16/126568 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786123 SCV000924785 uncertain significance not provided 2016-10-24 no assertion criteria provided provider interpretation p.Asp297Asn (c.889G>A) in the DSP gene (NM_004415.2) Seen in a patient with unexplained cardiac arrest and family history of sudden death and early-onset atrial fibrillation. Testing done by Invitae. Given its presence in controls and lack of case data, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Per our searches and the lab report, there is no case data available for this variant. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The aspartic acid at codon 297 is conserved across species. This variant is present in 10 of 60,683 individuals in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 2016). Specifically this variant was observed in 8 of 33340 individuals of European (non-Finnish) descent, 1 of 5202 individuals of African descent and 1 of 454 individuals of “other” descent. Of note, Kapplinger et al. (2011) from Michael Ackerman’s group have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants—similar to the 21% yield in 175 Dutch and U.S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC-related genes need to be interpreted with caution. Kapplinger et al. also report a “hot spot” for DSP variants between amino acids 250-604 in patients with ARVC but not in controls. Furthermore, in the ExAC constraint analyses, DSP appears to be fairly tolerant to missense variation (Z=0.91), but not to loss of function/truncating variation (pLI=1.000)

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